Prognostic factors for outcome in patients with refractory and relapsed acute lymphocytic leukemia treated with inotuzumab ozogamicin,a CD22 monoclonal antibody

Inotuzumab ozogamicin was found to be highly active in patients with refractory‐relapsed acute lymphocytic leukemia (ALL), with an overall response rate of 58% and a median survival of 6.3 months. Identifying factors associated with different outcomes on inotuzumab therapy may help select patients for this treatment and advice of prognosis. A total of 89 patients treated with inotuzumab on previous studies were analyzed. Inotuzumab was given at 1.3–1.8 mg/m² intravenously (IV) × 1 every 3–4 weeks or weekly (0.8 mg/m² day 1, 0.5 mg/m² days 8 and 15) every 3–4 weeks. Pretreatment factors associated with achieving marrow complete response (CR) and with survival were analyzed using standard statistical methods. The median survival of patients with at least marrow CR was 9.2 months versus 3.4 months for those without marrow CR (P < 0.001). By multivariate analysis, a high peripheral blood absolute blast count and low platelet count were independently associated with a lower likelihood of achieving at least marrow CR. Baseline characteristics independently associated with worse survival included adverse cytogenetics [complex karyotype, translocation (4;11), translocation (9;22), abnormal chromosome 17], disease beyond first salvage, and high peripheral blood absolute count. Patients with 0, 1–2, or 3 adverse factors had a median survival of 39+, 7.5, and 2.4 months, respectively. Our current analyses identified a subset of adult patients with ALL in whom outcome of therapy with inotuzumab ozogamicin can be differentially predicted. Am. J. Hematol. 90:193–196, 2015. © 2014 Wiley Periodicals, Inc.     

Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins

The paradigm that microtubule-targeting agents (MTAs) cause cell death via mitotic arrest applies to rapidly dividing cells but cannot explain MTA activity in slowly growing human cancers. Many preferred cancer regimens combine a MTA with a DNA-damaging agent (DDA). We hypothesized that MTAs synergize with DDAs by interfering with trafficking of DNA repair proteins on interphase microtubules. We investigated nine proteins involved in DNA repair: ATM, ATR, DNA-PK, Rad50, Mre11, p95/NBS1, p53, 53BP1, and p63. The proteins were sequestered in the cytoplasm by vincristine and paclitaxel but not by an aurora kinase inhibitor, colocalized with tubulin by confocal microscopy and coimmunoprecipitated with the microtubule motor dynein. Furthermore, adding MTAs to radiation, doxorubicin, or etoposide led to more sustained γ-H2AX levels. We conclude DNA damage-repair proteins traffic on microtubules and addition of MTAs sequesters them in the cytoplasm, explaining why MTA/DDA combinations are common anticancer regimens.First developed as anticancer agents in the 1950s, microtubule targeting agents (MTAs) are used in the treatment of a wide variety of malignancies and until now have been thought to kill cells by arresting them in mitosis (1, 2). Although this explanation applies to rapidly dividing cells in preclinical models, it cannot explain the activity of these agents in tumors in humans because these cells divide much more slowly. For the latter situtation, a different paradigm must explain the activity of MTAs, and we have proposed that interfering with microtubule (MT) trafficking in interphase cells is the principal mechanism of MTA action (3–5). In breast, ovarian, lung, and head and neck cancers, as well as in most lymphomas, combination regimens that include a MTA and a DNA-damaging agent (DDA) are preferred (Table S1). Although the frequency with which these combinations are used might be fortuitous, it is likely there is a mechanistic basis for this outcome. We hypothesized that by hampering the trafficking of essential DNA repair proteins, MTAs synergize with DDAs, augmenting their toxicity. To explore this theory further we studied the effects of combining a MTA and a DDA in a number of cell models and examined the distribution and biology of nine different proteins involved in DNA repair. We have confirmed the hypothesis and report our findings.     

Potassium Abnormalities in Current Clinical Practice: Frequency,Causes, Severity and Management

Objective

We aimed to investigate the prevalence and etiology of potassium abnormalities (hypokalemia and hyperkalemia) and management approaches for hospitalized patients.

Subjects and Methods

Over a 4-month period, all hospitalized patients at Hacettepe University Medical Faculty Hospitals who underwent at least one measurement of serum potassium during hospitalization were included. Data on serum levels of electrolytes, demographic characteristics, cause(s) of hospitalization, medications, etiology of potassium abnormality and treatment approaches were obtained from the hospital records.

Results

Of the 9,045 hospitalized patients, 1,265 (14.0s%) had a serum potassium abnormality; 604 (6.7s%) patients had hypokalemia and 661 (7.30s%) had hyperkalemia. In the hypokalemic patients, the most important reasons were gastrointestinal losses in 555 (91.8s%) patients and renal losses in 252 (41.7s%) patients. The most frequent treatment strategies were correcting the underlying cause and replacing the potassium deficit. Of the 604 hypokalemic patients, 319 (52.8s%) were normokalemic at hospital discharge. The most common reason for hyperkalemia was treatment with renin-angiotensin-aldosterone system blockers in 228 (34.4s%) patients, followed by renal failure in 191 (28.8s%). Two hundred and ninety-eight (45.0s%) patients were followed without any specific treatment. Of the 661 hyperkalemic patients, 324 (49.0s%) were normokalemic at hospital discharge.

Conclusion

This study showed a high prevalence of potassium imbalance among hospitalized patients. Although most of the potassium abnormalities were mild/moderate, approximately half of the patients treated for hypokalemia or hyperkalemia were discharged from the hospital with ongoing dyskalemia.Key Words: Hypokalemia, Hyperkalemia, Potassium     

Therapy response monitoring of the early effects of a new BRAF inhibitor on melanoma xenograft in mice: evaluation of 18F‐FDG‐PET and 18F‐FLT‐PET

Inhibition of the V600E mutated BRAF kinase gene (BRAF^V600E) is an important and effective approach to treating melanomas. A new specific small molecule inhibitor of BRAF^V600E, PLX3603, showed potent melanoma growth‐inhibiting characteristics in preclinical studies and is currently under clinical investigation. In this study we investigated the feasibility of ¹⁸F‐FDG and ¹⁸F‐FLT‐PET to monitor the early effects of the BRAF^V600E inhibitor in mice with melanoma xenografts. SCID/beige mice with subcutaneous (s.c.) A375 melanoma xenografts, expressing BRAF^V600E, received the BRAF^V600E inhibitor twice daily orally (0, 25, 50 and 75 mg/kg). At 1, 3 and 7 days after start of therapy, the uptake of ¹⁸F‐FDG and ¹⁸F‐FLT in the tumor and normal tissues was determined in ex vivo tissue samples. Serial ¹⁸F‐FDG and ¹⁸F‐FLT‐PET scans were acquired of animals at 1 day before and 1, 3 and 7 days after start of treatment with 75 mg/kg BRAF^V600E inhibitor. A dose‐dependent decrease in ¹⁸F‐FDG uptake in the A375 tumors was observed by ex vivo biodistribution analysis. Administration of 75 mg/kg BRAF inhibitor for 1, 3 and 7 days resulted in a significantly decreased ¹⁸F‐FDG uptake in A375 tumors (41, 35 and 51%, respectively). ¹⁸F‐FLT uptake in the A375 tumors was low at baseline and no significant changes in ¹⁸F‐FLT uptake were observed at any of the doses administered. These effects were corroborated by serial in vivo ¹⁸F‐FDG and ¹⁸F‐FLT‐PET imaging. These data demonstrate that ¹⁸F‐FDG‐PET can be used as an imaging biomarker to noninvasively evaluate the early effects of PLX3603. Copyright © 2014 John Wiley & Sons, Ltd.