scholarly journals A Pilot Study on Probing of Imatinib Induced Platelet Dysfunction in Patients with Chronic Myeloid Leukemia-Chronic Phase and Absence of Associated Bleeding Manifestation: Trying to Solve an Enigma

2020 ◽  
Author(s):  
Rajib De ◽  
Ranjini Chowdhury ◽  
Tuphan Kanti Dolai ◽  
Biswajit Bhar ◽  
Mohammad Mirazul Islam ◽  
...  
Keyword(s):  
Pilot Study ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Platelet Dysfunction ◽  
Bleeding Manifestation

scholarly journals Tyrosine kinase inhibitor–induced platelet dysfunction in patients with chronic myeloid leukemia

Blood ◽  
2009 ◽  
Vol 114 (2) ◽  
pp. 261-263 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Xin Han ◽  
Hagop Kantarjian ◽  
Jorge Cortes
Keyword(s):  
Platelet Aggregation ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Platelet Dysfunction ◽  
Normal Platelet ◽  
Closure Time ◽  
Platelet Aggregometry ◽  
Increased Risk

Abstract Dasatinib is associated with increased risk of bleeding among patients with chronic myeloid leukemia, even in the absence of thrombocytopenia, suggesting the presence of a hemostatic defect. We tested platelet aggregation in 91 patients with chronic myeloid leukemia in chronic phase either off-therapy (n = 4) or receiving dasatinib (n = 27), bosutinib (n = 32), imatinib (n = 19), or nilotinib (n = 9). All but 3 patients simultaneously receiving imatinib and warfarin had normal coagulation studies. All 4 patients off therapy had normal platelet aggregation. Impaired platelet aggregation on stimulation with arachidonic acid, epinephrine, or both was observed in 70%, 85%, and 59% of patients on dasatinib, respectively. Eighty-five percent of patients on bosutinib, 100% on nilotinib, and 33% on imatinib had normal platelet aggregation. Dasatinib 400 nM induced rapid and marked prolongation of closure time to collagen/epinephrine in normal whole blood on the PFA-100 system. In conclusion, dasatinib and, to some extent, imatinib produce abnormalities in platelet aggregometry testing.

K562/GM-CSF Immunotherapy as a “Booster” Vaccine In Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4347-4347
Author(s):  
Eunpi Cho ◽  
Hyam I. Levitsky ◽  
Jeanne Kowalski ◽  
Hua-Ling Tsai ◽  
Lu Qin ◽  
...  
Keyword(s):  
Pilot Study ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Burden ◽  
Chronic Phase ◽  
Booster Vaccination ◽  
Response To Therapy ◽  
Cell Mediated Immunity ◽  
Gm Csf ◽  
Best Response

Abstract Abstract 4347 Background: Chronic myeloid leukemia (CML) is a disease that is responsive to T-cell-mediated immunity. K562/granulocyte macrophage-colony stimulating factor (GM-CSF) is a vaccine derived from a CML cell line that produces GM-CSF and expresses several CML-associated antigens. An initial pilot study was performed in 19 patients in chronic phase CML who had achieved at least a major cytogenetic response on imatinib mesylate (IM) but had measurable molecular disease. The results suggested that immunotherapy resulted in a lowering tumor burden in the majority of patients (n = 13) with a total of 7 patients achieving undetectable bcr-abl levels by QT-PCR. (Smith, Clinical Cancer Research, 2010). This extension study evaluated the biologic impact of K562/GM-CSF given as a “booster” in subjects who completed the pilot study's scheduled 4 vaccinations and continued to have have persistent measurable disease or who lost their best response to the original therapy. Methods: This is a single-institution pilot study using open-label K562/GM-CSF vaccination as a “booster” in chronic phase CML patients who were previously treated with a full 4-vaccination course of therapy and continued to have measurable CML disease. Patients were stratified as having either responded to the initial set of vaccines and had subsequent loss of response or as having had no measurable response to therapy. None experienced significant adverse events in the first set of vaccinations. “Booster” treatment consisted of 4 doses of 1 × 108 irradiated K562/GM-CSF given every 3 weeks. Imatinib was continued through the study at the patients’ starting doses. Disease burden was measured using peripheral blood RT-PCR and FISH was every 3 months throughout the course of planned booster vaccinations for up to a year following the vaccination boost. Patients with evidence of advancing disease requiring adjustments to their IM dosing or those progressing to accelerated or blast phase were taken off study. Results: 11 patients met the eligibility to receive the booster vaccinations. Mean age was 54 (range 38–78) years. Median dose of IM therapy was 600 mg daily (range 400–800 mg). The median time from final vaccination in the pilot study to first booster vaccination was 24 (range 18–24) months. Duration of follow up was a median of 36 months (range 6–42 months). In general, the trend for lower disease burden following booster vaccines was significant by Generalize Estimating Equation using all study measures (p<0.009). Seven patients (63%) achieved their lowest levels of disease burden to date at a median of 5 (range 3–39) months following the initiation of their booster vaccinations with only 1 patient losing their “best” response as defined by a 10-fold increase in PCR value. One of the responding patients who had lost her complete molecular remission and became positive for 5 consecutive PCR readings prior to starting the booster immunizations was found to be undetectable after starting the booster treatments and has maintained negative PCR after the completion of the booster series (now at 1 year post booster). Three patients, all of whom qualified for the booster vaccines as “non-responders” to the initial immunizations, went off study secondary to progression of disease. Using sera from patients on the initial pilot study, antibodies against a total of 24 newly identified CML associated antigens were detected in post-vaccination > pre-vaccination samples. Of these, 15 antigens were recognized in 2 or more subjects. The influence of the vaccine boost series on antibody titer and on the induction of antibodies to antigens not previously recognized is under study. K562/GM-CSF immunotherapy given as a “booster” vaccination was associated with the lowering tumor burdens in 7 of 11 treated patients. Ongoing efforts to identify tumor-associated antigens that may be serving as immunologic targets is ongoing. Disclosures: Levitsky: HL vaccine: Patents & Royalties.

scholarly journals Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis

Leukemia ◽  
2021 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Timothy P. Hughes ◽  
Richard A. Larson ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Chronic Phase ◽  
Individual Treatment ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Treatment Free Remission

AbstractIn the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.

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