Chronic Myeloid Leukemia (CML)
Leukemia Insights - Summer 2008
The second generation tyrosine kinase inhibitors (TKIs) have demonstrated significant activity in all phases of CML post imatinib failure. Dasatinib (Sprycel), a dual Src-Abl inhibitor was approved by the FDA for this indication in June 2006. Nilotinib (Tasigna), a 50x more potent Bcr-Abl was approved by the FDA in July 2007. We have implemented frontline studies with both of these second generation TKIs for patients with newly diagnosed CML. The preliminary analyses show the superior activity of both agents compared with standard- and high-dose imatinib and a reasonable safety profile. Dasatinib is now given as 100 mg single oral daily dose. Nilotinib is given as 400 mg PO bid. The preliminary findings of both studies have been updated at the ASCO 2008 (JCO 26:abst. 7009 and 7010, 2008)
a. Dasatinib in newly diagnosed CML: protocol 2005-0422.
b. Nilotinib in newly diagnosed CML: protocol 2005-0048.
Both studies provide free drug supply and require a minimum initial stay (3-5 days) at M. D.
Anderson with 1 day visits q 3 months in year 1 and q 6 months thereafter.
CML Post Imatinib Failure
We are investigating a new dual Src-Abl 200x more potent inhibitor in this setting, bosutinib (SKI-606). The experience with bosutinib is very encouraging. Among patients in chronic phase CML post imatinib failure treated with bosutinib 500 mg daily the CHR rate is 89% and the major cytogenetic response rate is 40%, complete in 30%, after a median duration of treatment of only 3 months. Side-effects are minimal including grade 3-4 thrombocytopenia in only 14% and rash in 7%. No pleural effusions or significant myelosuppression have been noted. This was updated at ASCO 2008 (JCO 26:abst 7001, 2008). The study of bosutinib in CML post imatinib failure in all phases is open:
- Bosutinib in CML post imatinib failure: protocol 2005-0813.
CML with T315I Mutations
This mutation is notorious for its resistance to current TKIs including imatinib, nilotinib and dasatinib. Aurora kinase inhibitors with potent T315I and JAK2 inhibitory activities include: 1) AT9283 (IV infusion for 3-6 days); 2) XL228, and 3) PHA 739358. In addition homoharringtonine, an old drug with significant anti-CML activity, has shown activity in the setting of CML T315I. In CML chronic phase with T315I, HHT produced a CHR rate of 45% and a cytogenetic response rate of 27%. It is currently under investigation in this setting as well as in patients with failure to at least 2 TKIs (updated at ASCO 2008; JCO 26:abst. 7021, 2008)
a. AT9283 in refractory hematologic malignancies: protocol 2006-0177.
b. XL228: protocol 2007-0502.
c. Homoharringtonine in CML with T315I mutations: protocol 2006-0192.
Vaccine & Other Immune Modulating Strategies in CML
Vaccines in CML may be helpful in the setting of minimal residual disease to augment the host immunity and eradicate residual disease resistant to TKIs. This may provide the future hope for cure of CML without the need for continued therapy. We are testing 2 vaccines in CML in the setting of significant minimal residual disease (complete cytogenetic response but no major molecular response, i.e. QPCR > 0.1 and stable). The two vaccines include the synthetic peptide vaccine and the PR1 vaccine (if HLA A2 positive). The latter study is ongoing.