Yoshiro Uzuka

Treatment of acute myelogenous leukemia in adults with N4-behenoyl-1-β-D-arabinofuranosylcytosine

Forty‐five previously‐untreated adult patients with acute myelogenous leukemia (AML) were treated with N4‐behenoyl‐1‐β‐D‐arabinofuranosyl‐cytosine (BHAC) in a multi‐institutional cooperative study. Among 41 evaluable patients, 15 (36.6%) achieved complete remission (CR) and 10 (24.4%) achieved partial remission by daily administration of 3 to 8 mg/kg of BHAC. Higher daily doses (5 mg/kg or more) produced higher CR rates, and all of the CR were observed among the patients receiving a total BHAC dosage of 50 mg/kg or more in a period of 10 days or more. The side effects were mild and acceptable: nausea–anorexia was observed in 27% of the patients and vomiting in 17%. The results of this study thus indicate BHAC to be effective for remission induction of AML, and to deserve further clinical trials in combination with other anti‐leukemic drugs. Cancer 56: 1913‐1917, 1985.

Leukemic optic nerve involvement complicating central retinal artery occlusion

A 52-year-old man suffered from acute myelogenous leukemia with optic nerve involvement. Initially, unilateral optic disc edema was observed in his right eye, with moderately decreased visual acuity and an enlarged blind spot. Two weeks later, he noticed a sudden loss of vision that was caused by an onset of-central retinal artery occlusion. Thereafter, a mass on the optic disc, peripapillary retinal hemorrhage, and subretinal infiltrates were observed ophthalmoscopically. He was treated with orbital irradiation (30 Gy). Despite treatment, retinal circulation and visual acuity did not recover, and rubeosis iridis occurred after one month, followed by elevated intraocular pressure.

Phase I clinical and pharmacokinetic study of orally administeredN 4-palmitoyl-1-β-d-arabinofuranosylcytosine

A phase I study ofN4-palmitoyl-1-β-d-arabinofuranosylcytosine (PLAC) was conducted in 88 patients; 36 with solid tumors and 52 with hematological malignancies, using 2 different schedules. Schedule 1 employed a single oral administration and Schedule 2, 5-day consecutive daily oral administration. In Schedule 1, the daily dose was initiated with 1 mg kg−1 which was escalated up to 24 mg kg−1 according to the modified Fibonacci’s method. Side effects included nausea, vomiting and skin rashes, but myelosuppression was not seen within this dose range. In Schedule 2, the daily dose was started with 1 mg kg−1 which was escalated up to 24 mg kg−1. Major side effects were nausea, vomiting and amorexia, and mild myelosuppression was noted at 12 mg kg−1 or more. The dose-limiting toxicity was gastrointestinal toxicity, which appeared at 3.3 mg kg−1 or more and became frequent at 7 mg kg−1 or more. Pharmacokinetic study revealed that the plasma concentrations of PLAC and ara-C, obtained by the oral intake of 3.3 mg kg−1 or more of PLAC, were sufficient for these compounds to exert cytotoxic effects on various human leukemia cellsin vitro. Based on these observations and plausible mechanism of action of PLAC, further clinical study should be carried out in a treatment schedule of considerably prolonged administration period with 3.3–6 mg kg−1 day−1 of PLAC.

Fifty-five essential thrombocythemia patients follow-up study in single institution of Japan

Background: Report on the changes of diagnostic criteria since 1970 and correspondence due to the development of new therapeutic drugs during long term clinical period. Patients and method: The subjects were Fifty-five ET patients who were 21-95years old who newly diagnosed Sendai Blood Disease Center (renaming Sendai Tomita Hospital from March 2013) between 1991 year and 2010 year. As a substitute for bone biopsy for convenient diagnostic tool, we diagnosed essential thrombocythemia (ET) by the smear sample of bone marrow aspiration focusing on platelet production of megakaryocyte cytoplasm. Result: We classified megakaryocytes into 7 types (0 to 5 and U) with platelet counts in the cytoplasm. We named Type U which was filled and spilling out platelets from megakaryocyte. Type U was not observed in our experienced 25 chronic myeloid leukemia cases, 10 polycythemia vera cases and another hematologic malignancies. The proportion of seven types was Type 0 was 35.9%, type I 4.7%, type II 6.0%, type III 3.0%, type IV 0.8%, type NK 4.4% and type U was 45.2% respectively. 30 males and 25 females, the age at the time of diagnosis was the median 64 years and range 21 to 95 with 61.8% above the age 60 years. The observation periods was from 17 months to 303 months and the median was 94 months. The main goal in ET is to prevent thrombohemorrhagic complications and the same for older patients. The frailty of elderly people, 15 of the 19 patients who stopped receiving medical examination was brought about by falls and aspiration pneumonia which caused the physical condition to decrease, not accompanied by ET treatment. The cause of frailty in older ET patients was irrespective ET treatment, and so on based on risk-adapted therapy was necessary for older ET patients. Conclusion: Megakaryocytes of ET patients showed platelet-free production and overproduction of platelets in cytoplasm. Based on risk-adapted therapy was necessary for frail older ET patients. Correspondence to: Yoshiko Saito, Aoikai Sendai Hospital, Sendai city, Miyagi Prefecture Japan, Tel: (81)-22-380-1000, Fax: (81)22-244-5755, E-mail: sy33814@topaz.ocn.ne.jp / ysaitou@mgu.ac.jp

Noninvasive early detection of anthracycline‐induced cardiotoxicity in patients with hematologic malignancies using the phased tracking method

Anthracyclines are among the most effective and widely used anticancer drugs; however, their use is limited by serious cardiotoxicity. Early detection is necessary to prevent the high mortality rate associated with heart failure (HF). We evaluated cardiac function in 142 patients using conventional echocardiography and the phased tracking method (PTM), which was measured using the minute vibration and the rapid motion components, neither of which is recognized in standard M‐mode nor in tissue Doppler imaging. For systolic function comparison, we compared left ventricular ejection fraction (LVEF) in conventional echocardiography with the average velocity of ventricular septum myocytes (Vave) in the PTM. The Vave of 12 healthy volunteers was 1.5 (m/s)/m or more. At baseline of 99 patients, there was a positive correlation between LVEF and Vave in all patients. There were no significant differences in baseline cardiac function between patients with and without HF. There was a negative correlation between the cumulative anthracycline dose and LVEF or Vave among all patients. We determined that Vave 1.5 (m/s)/m was equivalent to LVEF 60%, 1.25 (m/s)/m to 55%, and 1.0 (m/s)/m to 50%. During the follow‐up period, there was a pathological decrease in LVEF (<55%) and Vave (<1.25 m/s/m) in patients with HF; decreases in Vave were detected significantly earlier than those in LVEF (P < 0.001). When Vave declined to 1.5 (m/s)/m or less, careful continuous observation and cardiac examination was required. When Vave further declined to 1.0 (m/s)/m or lower, chemotherapy was postponed or discontinued; thus, serious drug‐induced cardiomyopathy was avoided in patients who did not relapse. The PTM was superior to echocardiography for early, noninvasive detection and intermediate‐term monitoring of left ventricle systolic function associated with anthracycline chemotherapy, among patients with hematologic malignancies. The PTM was an effective laboratory procedure to avoid the progression to serious cardiomyopathy.

Phase I clinical and pharmacokinetic study ofN 4-behenoyl-1-β-d-arabinofuranosylcytosine

A phase I study ofN4-behenoyl-1-β-d-arabinofuranosylcytosine (BHAC) was conducted in 66 patients, 41 with solid tumors and 25 with hematological malignancies. The patients received either a 2-h single intravenous (i.v.) drip infusion (Schedule 1) or consecutive daily 2-h i.v. infusions (Schedule 2). In Schedule 1 the daily dose was initiated with 1.5 mg kg−1 which was escalated up to 7 mg kg−1. Side-effects were mild, and included nausea, vomiting, epilation, and hot flushes. Because of the presence of the solvent vehicle, HCO-60 and in consideration of the mechanism of action of BHAC, the dose escalation was stopped at 7 mg kg−1. In Schedule 2, the daily dose was started with 1.5 mg kg−1 which was escalated up to 8 mg kg−1 and given for 2–16 days. Myelosuppression was found to be dose-limiting toxicity. The maximum tolerated dose (MTD) in patients with non-hematological solid tumors was assumed to be 5 mg kg−1 daily × 5 days. The plasma disappearance curve of BHAC looked biphasic, and when 4 mg kg−1 of BHAC were administered the half-lives of the initial phase (t1/2α) and the second phase (t1/2β) were calculated as 0.798 and 5.76 h respectively. In Schedule 2 complete remission was observed in 5 out of 21 patients with acute leukemia, one partial remission in Hodgkin’s disease, and one 1-B response (Karnofsky) in thyroid papillary adenocarcinoma.