Gemtuzumab ozogamicin in acute myeloid leukemia.

CD33 is variably expressed on leukemia blasts in almost all patients with acute myeloid leukemia (AML) and possibly leukemia stem cells in some. Efforts to target CD33 therapeutically have focused on gemtuzumab ozogamicin (GO; Mylotarg), an antibody-drug conjugate delivering a DNA-damaging calicheamicin derivative. GO is most effective in acute promyelocytic leukemia but induces remissions in other AML types and received accelerated approval in the US in 2000. However, because a large follow-up study showed no survival improvement and increased early deaths the drug manufacturer voluntarily withdrew the US New Drug Application in 2010. More recently, a meta-analysis of data from several trials reported better survival in adults with favorable- and intermediate-risk cytogenetics but not adverse-risk AML randomized to receive GO along with intensive induction chemotherapy. As a result, GO is being re-evaluated by regulatory agencies. Responses to GO are diverse and predictive biological response markers are needed. Besides cytogenetic risk, ATP-binding cassette transporter activity and possibly CD33 display on AML blasts may predict response, but established clinical assays and prospective validation are lacking. Single-nucleotide polymorphisms in CD33 may also be predictive, most notably rs12459419 where the minor T-allele leads to decreased display of full-length CD33 and preferential translation of a splice variant not recognized by GO. Data from retrospective analyses suggest only patients with the rs12459419 CC genotype may benefit from GO therapy but confirmation is needed. Most important may be markers for AML cell sensitivity to calicheamicin, which varies over 100 000-fold, but useful assays are unavailable. Novel CD33-targeted drugs may overcome some of GO's limitations but it is currently unknown whether such drugs will be more effective in patients benefitting from GO and/or improve outcomes in patients not benefitting from GO, and what the supportive care requirements will be to enable their safe use.

Comparison of minimal residual disease as outcome predictor for AML patients in first complete remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation.

Minimal residual disease (MRD) is associated with adverse outcome in acute myeloid leukemia (AML) after myeloablative (MA) hematopoietic cell transplantation (HCT). We compared this association with that seen after nonmyeloablative (NMA) conditioning in 241 adults receiving NMA (n=86) or MA (n=155) HCT for AML in first remission with pre-HCT bone marrow aspirates assessed by flow cytometry. NMA patients were older and had more comorbidities and secondary leukemias. Three-year relapse estimates were 28% and 57% for MRD(neg) and MRD(pos) NMA patients, and 22% and 63% for MA patients. Three-year overall survival (OS) estimates were 48% and 41% for MRD(neg) and MRD(pos) NMA patients and 76% and 25% for MA patients. This similar OS after NMA conditioning was largely accounted for by higher non-relapse mortality (NRM) in MRD(neg) (30%) compared with MRD(pos) (10%) patients, whereas the reverse was found for MRD(neg) (7%) and MRD(pos) (23%) MA patients. A statistically significant difference between MA and NMA patients in the association of MRD with OS (P<0.001) and NRM (P=0.002) but not relapse (P=0.17) was confirmed. After adjustment, the risk of relapse was 4.51 times (P<0.001) higher for MRD(pos) patients. These data indicate that the negative impact of MRD on relapse risk is similar after NMA and MA conditioning.

Predictive value of the dexamethasone suppression test in mania.

Eighteen manic patients who had abnormal results on the dexamethasone suppression test at admission were retested before discharge, when they were clinically stable. Conversion to normal suppression predicted good outcome after discharge, whereas a persistently abnormal test predicted poor outcome.

The dexamethasone suppression test in acute mania.

The dexamethasone suppression test was administered to 40 newly admitted manic patients. Twenty-four patients (60%) had abnormal escape from suppression. There was no correlation of DST results with sex, age, age of onset, family history of affective disorder, psychosis during index episode, or duration of hospitalization. DST non-suppressors were significantly more likely than suppressors to be discharged on lithium alone.

Lithium-carbamazepine neurotoxicity and risk factors.

Five rapid-cycling manic patients developed neurotoxic syndromes when treated with a combination of lithium and carbamazepine, although all five had therapeutic plasma levels of both drugs. The risk factors for development of neurotoxicity with this drug combination are discussed.

Consistent dexamethasone suppression test results with mania and depression in bipolar illness.

Dexamethasone suppression tests (DSTs) were given to nine bipolar patients in both depressed and manic phases of their illness. In seven patients DST results were consistent between episodes; six patients had positive tests in both depression and mania.

Case report of tricyclic-induced delirium at a therapeutic drug concentration.

A patient receiving a standard dose of imipramine developed a drug-induced delirium. Her plasma antidepressant level was in the low therapeutic range. Thus, tricyclic-induced delirium may in some cases be an idiosyncratic phenomenon unrelated to plasma drug concentration.