Overt failure is defined as a loss of hematologic remission or progression to accelerated-phase or blast-crisis phase chronic myelogenous leukemia (CML) as previously defined. A consistently rising quantitative reverse–transcription polymerase chain reaction BCR/ABL level suggests relapsing disease. For initial use of imatinib mesylate, the designation of relative failure or suboptimal response has been proposed for lack of complete hematologic remission by 3 months, no cytogenetic response by 6 months, or no major cytogenetic response by 12 months.[1,2] Nilotinib and dasatinib induce such high rates of complete cytogenetic responses and major molecular responses within several months that new benchmarks are required for responsiveness. These investigators propose that a complete cytogenetic response by 3 months should define an optimal response.[3,4]
In case of treatment failure or suboptimal response, patients should undergo BCR/ABL kinase domain mutation analysis to help guide therapy with the newer tyrosine kinase inhibitors or with allogeneic transplantation.[5,6] Mutations in the tyrosine kinase domain can confer resistance to imatinib mesylate; alternative inhibitors such as dasatinib, nilotinib, or bosutinib, higher doses of imatinib mesylate, and allogeneic stem cell transplantation (SCT) have been studied in this setting.[7,8,9,10,11,12,13,14,15,16,17,18,19] In particular, the T315I mutation marks resistance to imatinib, dasatinib, nilotinib, and bosutinib. In a phase I escalation study with 81 patients, patients with the T315I mutation responded to ponatinib, an oral tyrosine kinase inhibitor.[Level of evidence: 3iiiDiv] Ponatinib also has activity in heavily pretreated-resistant CML and in a third of the patients with accelerated-phase or blast-crisis phase CML. Clinical trial participation should help establish the optimal sequence of these options.
The age-adjusted incidence of carcinoid tumors worldwide is approximately 2 per 100,000 persons.[1,2] The average age at diagnosis is 61.4 years. Carcinoid tumors represent about 0.5% of all newly diagnosed malignancies.[2,3]
Carcinoid tumors are rare, slow-growing tumors that originate in cells of the diffuse neuroendocrine system. They occur most frequently in tissues derived from the embryonic gut. Foregut tumors, which account for up to 25% of cases, arise...
Infusions of buffy-coat leukocytes or isolated T cells obtained by pheresis from the bone marrow transplant donor have induced long-term remissions in more than 50% of patients who relapse following allogeneic transplant.[21,22] The efficacy of this treatment is thought to be the result of an immunologic graft-versus-leukemia effect. This treatment is most effective for patients whose relapse is detectable only by cytogenetics or molecular studies and is associated with significant graft-versus-host disease. After relapse from allogeneic SCT, some patients will also respond to interferon alpha. Most patients will respond to imatinib mesylate with durable (>1 year) cytogenetic and molecular responses. (These patients had not previously received imatinib.)[24,25,26]