ALBERT

Description: 1. Saccharated ferric oxide in colloidal suspension was administered intravenously on 17 occasions to 13 patients in doses of 100 to 1,000 mg. A prompt arterial leukopenia, followed within 30 to 90 seconds by a similar fall in the venous blood, was observed in all patients who received more than 200 mg. of iron. This leukopenia involved all white cell types. 2. The magnitude of the fall in leukocytes was directly proportional to the amount of material injected, and independent of the rate of injection under the conditions of the study. 3. There was no significant change in the platelet number in arterial or venous blood of 4 patients. In 2 patients an increased clotting power of venous blood containing large amounts of iron was observed only during the period of injection. 4. The colloidal nature of the material is probably the responsible factor in producing the leukopenia.

Description: Key Points Mer tyrosine kinase is aberrantly expressed in ∼30% of pediatric pre–B-ALL patients, including most patients with an E2A-PBX1 translocation. Mer inhibition decreased B-ALL cell survival signal transduction, caused chemosensitization, and prolonged survival in a xenograft model.

Description: This prospective multicenter study examined whether simultaneous administration of granulocyte colony-stimulating factor (G-CSF; Filgrastim) and induction chemotherapy for adult acute lymphoblastic leukemia (ALL) could prevent treatment-related neutropenia, infections, and resulting treatment delays. Seventy-six patients were randomly assigned to receive either G-CSF (n = 37) or no growth factor (n = 39) in conjunction with a uniform chemotherapy consisting of cyclophosphamide, cytarabine, mercaptopurine, intrathecal methotrexate, and cranial irradiation. The median duration of neutropenia (absolute neutrophil count 〈 1 x 10(9)/L) during chemotherapy was 8 days in patients receiving C-CSF, compared with 12.5 days in the control group (P 〈 .002). A similar reduction from 11.5 to 7 days was observed in patients with T-ALL receiving additional mediastinal irradiation (P = .13). Infections occurred in 43% and 56% of patients in the G-CSF and control arm, respectively (P = .25); the incidence of nonviral infections was reduced by 50%, from 32 episodes in the control arm to 16 episodes in the G-CSF arm. Prolonged interruptions of chemotherapy administration were less frequent, with delays of 2 weeks or more occurring in only 24% of patients receiving G-CSF as opposed to 46% in the control arm (P = .01). Accordingly, chemotherapy was completed significantly earlier with the use of G-CSF (39 v 44 days, P = .008). With a median follow-up of 20 months, the probability of disease-free survival was 0.45 in the G-CSF group and 0.43 in the control group (P = .34). In conclusion, adult ALL patients appear to benefit by the simultaneous administration of G-CSF with induction chemotherapy because of a significant reduction in the duration of neutropenia, a trend to fewer infections, and a more rapid completion of chemotherapy.

Description: Eleven patients with leukemia and one patient with myeloid metaplasia underwent leukapheresis on 18 occasions for 94 to 275 minutes during which 93 to 1668 x 109 leukocytes were removed. All patients exhibited a significant and continued decline of peripheral leukocyte concentration during or after the procedure. In 12 of the 18 instances, the leukocyte concentration returned slowly to the initial leukocyte level within 1 hour to 22 days. The number of leukocytes withdrawn represented 16 to 247 per cent of the initial circulating volume removed at a rate of 0.13 to 1.14 leukocyte blood volumes per hour. The RAR was 1:1 to 12:1 to the circulating leukocyte number. Rate of replenishment of the circulating immature leukocyte numbers were 4.0 x 107 to 52.2 x 109/Kg./day. The PMN’s were replaced at rates of 10 x 106 to 7.05 x 109/Kg./day which were equal to or slower than in normal subjects. Changes in number occurred in the dominant leukemic cell types without significant shifts in the differential counts. No changes in marrow population other than a slight decrease in cellularity were observed. The data indicate that in the leukemic patient the peripheral leukocyte concentration was not maintained or replenished promptly following the withdrawal of sizeable quantities of leukocytes, demonstrating a block in transfer of leukocytes from the tissues to the blood. This is in marked contrast to the leukocytosis and marrow stimulation observed in hematopoietically normal subjects following leukaphereses. The platelet counts fell promptly during leukapheresis, returning toward control levels in eight studies within 7 hours following the procedure. In four studies the platelet counts returned to control levels in 3 to 9 days. The changes in platelet concentrations were similar to those observed with hematologically normal subjects. The size of the platelet reservoir in these leukemic patients is about twice that of the circulating blood.

Description: Introduction: Clinically relevant outcomes as improvements in overall survival (OS) or quality of life (QOL) should guide decision-making. The FDA encourages the implementation of patient-centric PRO measures in clinical trials. In the recent decade there have been a growing number of protocols including PROs in their outcome measures, and an increase in pre-market submissions including those measures. We aimed to evaluate the frequency at which PRO measures, incorporated into clinical trials, are made publicly available, when trial results are published. Methods: We searched Citeline® Trialtrove database, a registry of clinical trials, for randomized phase 2/3 and 3 clinical trials including patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), initiated between the years 2005-2015, with PRO endpoints listed. We excluded trials involving patients with acute leukemia or involving stem cell transplantation. For these trials we recorded the following data: indication, treatment and comparator, phase, primary endpoint, type of scale or questionnaire used for PRO endpoint. We then identified all available publications associated with the trial, and recoded type of publication (abstract or full text), year, number of randomized patients, reported outcomes. Results: 120 CLL and NHL trials were identified through our search. 44 trials (23 CLL, 21 NHL) were listed with at least one PRO endpoint. Eleven trials were excluded (1 extension of an included trial, 4 not completed, 4 not published, 2 cancelled with little or no recruitment). PRO endpoints were assessed utilizing - EORTC-QLQ30 QoL, QLQ-CLL16, FACIT-fatigue, FACT-leu, FACT-lym, EQ-5D, Skindex-29, and Rituximab Administration Satisfaction Questionnaire as relevant per indication. PRO was the primary outcome in two trials, and secondary in the other 31. Study sponsor was industry-only in 27 trials, and industry-academic in five. Of the 33 trials analyzed, 14 (42%) published results of the PRO endpoint - 6/17 (35%) of CLL trials, and 8/16 (50%) of NHL trials. 26/33 of the trials were published as full-text, 6/33 as abstract, and 1 published on clinicaltrials.gov. Of the 26 full text publications, 12 (46%) reported PRO. In 8 of full-text PRO were reported as part of the primary publication or published within 6 months. Nine of all trials provided a comprehensive report of PRO endpoints. Of the 33 trials, only 2 provided information about missing PRO data. 54% of trials in which primary endpoint was reached, and 12.5% of trials in which it was not reached, were published listing PRO results. Of the trials that showed PFS benefit, with no OS benefit, 9/15 (60%) published the results of the PRO endpoints. Conclusions: Despite a growing emphasis on QOL and use of PROs in oncology clinical trials, and despite patient and health provider efforts to record PRO data, most CLL and NHL randomized trials still do not report the PRO endpoints. In several cases they were published later and in a partial manner, minimizing their impact on treatment decisions. This may indicate a disregard to PRO data collected, incomplete collection or methodological flaws in data analysis. Regardless of the reason, PRO data should be routinely included in study publications to allow for a complete assessment of investigational treatment outcome - including disease related outcomes, as well as those reported by the patients themselves. Table 1. Table 1. Disclosures No relevant conflicts of interest to declare.

Description: 1. The leukocyte and platelet contents of arterial and venous blood of 12 patients were determined simultaneously during and following the intravenous administration of 0.1 to 0.3 mg. of epinephrine, l-epinephrine or norepinephrine. 2. Within 30 to 60 seconds after the start of the epinephrine administration, an initial arterial leukocytosis and thrombocytosis occurred in 10 and 8 instances respectively and continued for at least 5 minutes before it declined. A leukocytosis also occurred in the venous blood but followed the arterial rise by 30 to 120 seconds. 3. It is concluded that the initial phase of the leukocytosis and thrombocytosis following intravenous epinephrine infusion is primarily from the pulmonary circulation. 4. The data indicate that the pulmonary circulation in man is a sizable reservoir of leukocytes and platelets which may be readily discharged into the circulation under proper stimulation.

Description: 1. The leukocyte content of venous and arterial blood of 17 subjects was studied repeatedly and frequently during respirations and the Valsalva and Muller maneuvers. The venous and arterial samples were drawn simultaneously and were obtained by direct puncture from freely-flowing peripheral veins or arteries or by catheterization from the right ventricle, pulmonary artery, hepatic vein, left ventricle or aorta. 2. During the Valsalva maneuver, the arterial leukocyte count decreased markedly with relatively little alteration in the simultaneous venous counts; upon release of the forced expiration both counts promptly regained the control level. 3. During the Muller maneuver, increases in both arterial and venous leukocyte counts occurred in one patient, while no significant effect was observed in venous samples in a second subject. 4. During inspiration the arterial leukocyte count fell and the simultaneous venous count rose with reciprocal changes upon expiration. These changes occurred whether the initial counts were elevated, normal or leukopenic. 5. The changes in leukocyte number of both arterial and venous blood during respiratory movements are not due to hemoconcentration or hemodilution and suggest a tidal ebb and flow of leukocytes into and from the pulmonary circulation of a significant degree.

Description: Eight patients with widespread metastatic neoplastic diseases following leukopoietic stimulation by leukapheresis were treated on 10 occasions with large doses of HN2, 30 to 280 mg. (0.6 to 4.1 mg./Kg.). Despite severe hematodepression with anemia, leukopenia and thrombocytopenia, hematopoietic recovery occurred in all instances within 16 to 25 days. The recovery from severe hematodepressant doses of HN2 is attributed largely to the previous leukopoietic stimulation. Doses of HN2 at approximately four times the LD50 were unable to eradicate metastatic tissue in Ewings sarcoma and malignant melanoma. Although hematopoietic protection was evident, the hazard of injuring the next most vulnerable tissues must be considered as larger amounts of cytotoxic agents are employed.

Description: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although cure rates have increased in recent years, significant risk of both short- and long-term toxicities persists including a 25% incidence of a severe late effect in pediatric cancer survivors. Thus, novel and less toxic therapies are needed. Most pediatric leukemias are of the B-cell lineage and a subset of these express the fusion protein E2A-PBX1 as a result of the chromosomal rearrangement t(1;19). A previous DNA microarray study suggested that the receptor tyrosine kinase Mer (MerTK) is aberrantly expressed in E2A-PBX1+ B-ALL (Yeoh et al., 2002, Cancer Cell 1:133–143). Within the hematopoietic lineages, MerTK is expressed in dendritic cells, monocytes/macrophages, NK cells, NKT cells, megakaryocytes, and platelets. However, MerTK is not expressed in normal lymphocytes. In studies of T-cell ALL, we have previously shown that ectopic expression of MerTK contributes to leukemogenesis. MerTK is known to activate anti-apoptotic signaling proteins such as Akt and Erk 1/2. These data led us to hypothesize that abnormal expression and activation of MerTK may provide a survival advantage for leukemia cells. Furthermore, inhibition of MerTK may enhance the sensitivity of leukemia cells to cytotoxic agents. In this study, we extended the findings of Yeoh et al. (2002) by confirming the ectopic expression of MerTK mRNA and protein in patient samples and human cell lines of E2A-PBX1+ B-ALL. In subsequent studies, we used lentiviral short hairpin RNA (shRNA) contructs to knockdown MerTK in the human E2A-PBX1+ B-ALL cell line, 697. In vitro assays of cell proliferation and survival demonstrated that inhibition of MerTK significantly increased the sensitivity of 697 cells to numerous chemotherapeutic agents. For example, when wildtype or non-silencing shRNA control (shControl) 697 cells were treated with 6-mercaptopurine (6-MP), an IC50 could not be determined because the cells were robustly resistant to killing with this agent. However, the MerTK knockdown lines demonstrated remarkable sensitivity (IC50 values ~ 4 μM) to 6-MP. In other cases, the wildtype/shControl 697 lines were sensitive to treatment with chemotherapeutic agents but a dramatic increase in sensitivity was observed with MerTK inhibition. These results were acquired via an assay of metabolically active cells which precludes determination of the contribution of changes in cell proliferation and cell death. To more specifically evaluate the role of cell death, we performed flow cytometric analysis of cells stained with propidium iodide and YO-PRO®-1. These experiments revealed that inhibition of MerTK results in increased induction of cell death in response to treatment with chemotherapeutic agents. Western blotting was used to compare the signaling pathways activated in shControl versus MerTK knockdown 697 cells following treatment with chemotherapeutic agents. Inhibition of MerTK leads to loss of ERK 1/2 and mTOR signaling in 697 cells. Further investigation demonstrated that inhibition of MerTK also correlates with robust activation of apoptotic proteins in response to treatment with chemotherapeutic agents. Specifically, cleavage of both Caspase 8 and Caspase 9 was observed suggesting that inhibition of MerTK permits activation of both intrinsic and extrinsic apoptosis pathways in response to treatment with chemotherapeutic agents. Taken together, these in vitro results suggest that inhibition of MerTK may increase the efficacy of standard chemotherapy and thereby allow for dose reduction and decreased toxicity. To demonstrate proof of concept in an in vivo setting, we evaluated the oncogenicity of wildtype, shControl and MerTK knockdown 697 cells in a mouse xenograft model of leukemia. We found that MerTK inhibition significantly delayed the onset of disease. Animals which received wildtype or shControl 697 cells exhibited median survival of 22 and 26 days, respectively. Median survival was significantly increased to 63 days for each of two clonal MerTK knockdown lines (P