Chronic Myeloid Leukemia (CML)
Leukemia Insights - Spring 2007
Newly Diagnosed CML
The second generation tyrosine kinase inhibitors (TKIs) have demonstrated significant activity in all phases of CML post imatinib failure. Dasatinib (Sprycel; BMS354825), a dual Src-Abl inhibitor was approved by the FDA for this indication in June 2006. Nilotinib (Tasigna; AMN107), a more potent Bcr-Abl inhibitor is expected to receive FDA approval in 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 given as 100 mg single daily dose PO vs 50 mg b.i.d. Nilotinib is given as 400 mg PO bid. The preliminary findings of both studies have been reported at the ASH 2006 (Blood 108:abstracts 2161 & 2172, 2006).
- Dasatinib in newly diagnosed CML – protocol 2005-0422
- 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 have completed the studies with dasatinib and nilotinib which are now available either commercially or on an expanded access program. We are currently investigating two dual Src-Abl inhibitors in this setting: bosutinib (SKI-606) and INNO-406. The experience with bosutinib is already very encouraging. Among 48 patients in chronic phase CML post imatinib failure treated with bosutinib 400 – 600 mg daily the CHR rate is 84% and the major cytogenetic response rate is 52% (complete in 33%) after a median duration of treatment of only 3 months. Side-effects are minimal including grade 3-4 thrombocytopenia in only 6% and rash in 6%. No pleural effusions or significant myelosuppression have been noted. This has been reported at ASH 2006 (Cortes.
Blood 108:abstract 168, 2006). This study of bosutinib in CML post imatinib failure in all phases is open. A phase I study of INNO-406, a Lyn and Abl inhibitor is also open, without any evidence of dose limiting toxicity at doses that are already inducing cytogenetic responses.
- Bosutinib in CML post imatinib failure – protocol 2005-0813
- INNO-406 in CML post imatinib failure – protocol 2006-0278
CML with T315I Mutations
This mutation is notorious for its resistance to existing classical TKIs including imatinib, nilotinib and dasatinib. MK0457, a new multi-kinase inhibitor, including aurora kinase and Abl, was found to have significant activity in CML with T315I mutations. Among 11 patients with CML in transformation with T315I treated with MK0457 at 8-32 mg/m2 per hour x 5 days, 5 achieved solid objective responses: 1 cytogenetic CR, 2 cytogenetic PRs, 1 minor cytogenetic response and 1 hematologic response. These studies of MK0457 in this setting as well as in acute leukemias and refractory hematologic malignancies are ongoing. Of note, MK0457 is also a notable JAK2 inhibitor and may benefit patients with JAK2 mutations refractory to standard therapy (PV, ET, myelofibrosis).
The preliminary results have been reported at ASH 2006 (Giles. Blood 108:abstract 163, 2006).
Other aurora kinase inhibitors with potent T315I and JAK2 inhibitory activities include AT9283 (IV infusion for 3 days) and KW2449 (oral daily therapy). In addition homoharringtonine, an old drug with significant anti-CML activity, has shown activity in the setting of CML T315I. It is currently under investigation in this setting as well as in patients with failure to at least 2 TKIs.
- MK0457 in CML T315I and other hematologic malignancies – protocol 2006-0992
- AT9283 in refractory hematologic malignancies – protocol 2006-0177
- KW2449 in refractory hematologic malignancies – protocol 2006-0275
- 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 (Scheinberg vaccine) and the PR1 vaccine (if HLA A2 positive). The 2 vaccine studies are ongoing in protocols 2005-0392 and 2006-0360.