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Prior studies suggest increased cytomegalovirus (CMV) infection after haploidentical donor transplantation with posttransplant cyclophosphamide (HaploCy). The role of allograft source and posttransplant cyclophosphamide (PTCy) in CMV infection is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection, and effects of serostatus and CMV infection on transplant outcomes. We examined patients reported to the Center for International Blood and Marrow Transplantation Research between 2012 and 2017 who had received HaploCy (n = 757), matched related (Sib) with PTCy (SibCy, n = 403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n = 1605). Cumulative incidences of CMV infection by day 180 were 42%, 37%, and 23%, respectively (P < .001). CMV disease was statistically comparable. CMV infection risk was highest for CMV-seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor (HaploCy [n = 545]: hazard ratio [HR], 50.3; SibCy [n = 279]: HR, 47.7; SibCNI [n = 1065]: HR, 24.4; P < .001). D+/R− patients also had increased risk for CMV infection. Among R+ or those developing CMV infection, HaploCy had worse overall survival and nonrelapse mortality. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic graft-versus-host disease (GVHD) overall, but CMV infection in PTCy recipients was associated with higher chronic GVHD (P = .006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally, CMV infection may negate the chronic GVHD protection of PTCy. This study supports aggressive prevention strategies in all receiving PTCy.

Background: Allogeneic HCT continues to be the optimal consolidation strategy for many patients with AML. Cytogenetic and molecular abnormalities are known to influence post-transplant outcomes. We tested the prognostic ability of a modified (mELN) classification system based on available CIBMTR genetic data, to predict post-transplant outcomes. Methods: Adult patients with a diagnosis of AML in first complete remission (CR1) with available pre-transplant cytogenetic and molecular mutational data, receiving a first allogeneic HCT from 2013-2017, were included. Patients were stratified according to mELN genetic classification in three distinct groups: favorable (Fav), intermediate (IM) and adverse (Adv). Clinical outcomes following HCT were compared among groups after adjusting for significant patient, disease, and transplant-related variables. The primary endpoint was disease free survival (DFS). Secondary endpoints were overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse, acute GVHD, and chronic GVHD. Cox proportional hazard models were used to compare endpoints among mELN risk groups, age groups and genetic subsets within the adverse-risk group. Results: Demographic characteristics are summarized in Table 1. 2289 patients (Fav, n=181; IM n=1185; and Adv n=923) met the inclusion criteria. Median follow-up for survivors was 35 months. Importantly, 41% of transplant recipients (n=936) were >60 years, 76% (n=1743) had de novo AML and 48% (n=1111) received a myeloablative conditioning regimen. Univariate analysis (UVA) demonstrated significant differences in 2-year OS (Fav: 67.7%, IM: 64.9% and Adv: 53.9%; p Initial multivariate analysis (MVA) of mELN risk groups indicated that there was no significant difference in clinical outcomes between the Fav and IM risk groups. Thus, these groups were combined for subsequent analyses. Adv risk (vs. Fav/IM) led to significantly worse OS (HR 1.39 [1.24-1.57] p= This mELN classification effectively stratified both younger (60 y/o) patients for OS (Adv vs. Fav/IM HR for 60: 1.44 [1.21-1.72] p60: 1.41 [1.19-1.66] p60: 1.42 [1.15-1.76] p=0.001). NRM was higher for older patients (>60 y/o) in both the Fav/IM (HR 1.40 [1.10-1.78] p=0.007) and Adv-risk cohorts (HR 1.59 [1.18-2.13] p=0.002). Genetic subset comparisons within the adverse-risk group showed that patients carrying monosomy 5, del(5q) or monosomy 7 had inferior 2-year OS (42.6%, p Conclusion: Stratification using mELN criteria resulted in clear prognostic separation of OS, DFS and relapse in this large cohort of AML patients undergoing allogeneic HCT. While Fav and IM groups had similar OS, DFS and relapse rates; patients in the Adv risk group had the highest risk of relapse and inferior DFS/OS. However, the majority of patients in all cohorts had favorable outcomes for HCT in CR1. Our findings confirm the value of a combined genetic prognostic model in the AML HCT setting and justify the use of this stratification system in future HCT trials. Correlation of genetic subtypes with other important transplant variables, such as conditioning intensity and pre-transplant MRD status deserves further evaluation. There remains a subset of Adv-risk patients for which post-transplant outcomes continue to be poor, even when transplanted in CR1. Novel peri-transplant pre-emptive/therapeutic strategies are urgently needed for this high-risk cohort. Disclosures de Lima: Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding; BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board. Komanduri:Kiadis: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kebriaei:Ziopharm: Other: Research Support; Jazz: Consultancy; Kite: Other: Served on advisory board; Amgen: Other: Research Support; Novartis: Other: Served on advisory board; Pfizer: Other: Served on advisory board. Bhatt:National Marrow Donor Program: Research Funding; Rigel Pharmaceuticals: Other; Jazz: Research Funding; Agios: Other: Personal Fees; Incyte: Other: Personal Fees, Research Funding; Takeda: Other: Personal Fees; Partner Therapeutics: Other: Personal Fees; Pfizer: Other, Research Funding; CSL Behring: Other; Tolero Pharmaceuticals: Research Funding; Oncoceutics: Other: Drug support for a trial; Partnership for health analytic research, LLC: Other: Personal Fees; Omeros: Other: Personal Fees; Abbvie: Other: Personal Fees, Research Funding. Saad:Orcabio: Other: research support; Kadmon: Other: research support; Amgen: Other: research support; Incyte Pharmaceuticals: Other: Personal Fees; Magenta Therapeutics: Other: Personal Fees. Copelan:Amgen: Membership on an entity's Board of Directors or advisory committees. Defilipp:Incyte: Research Funding; Regimmune: Research Funding; Syndax Pharmaceuticals: Consultancy. Nishihori:Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy.

Background: Historically, Kentucky has had one of the highest rates of cancer mortality in USA. In non-hematologic malignancy, the Appalachian region of the eastern United States is also associated with poor outcomes, however, the relationship with hematologic malignancy is poorly understood. We aim to study the disparities of Plasma Cell Neoplasms (PCN) in this region utilizing the Surveillance, Epidemiology, and End Results Program (SEER) database. Methods: We identified patients with PCN (multiple myeloma [MM], solitary plasmacytomas [PC], and plasma cell leukemia [PCL]) from the SEER database between 2000-2015. Data obtained included demographics, state, residence in an Appalachian region, rural/urban continuum code, median annual household income, and overall survival (OS) outcomes. Kentucky and Georgia are the only states that report to SEER which have populations from Appalachia. Therefore, patients were classified into 5 groups: Appalachia/Kentucky, non-Appalachia/Kentucky, Appalachia/Georgia, non-Appalachia/Georgia, and other (non-Appalachian) states. We used Kaplan-Meier & Cox regression to analyze survival outcomes. Income was analyzed as a continuous variable. Variables with a p value < 0.1 in univariate analysis were included in a stepwise multivariate Cox proportional hazard ratio (HR) model. Results A total of 68,627 patients were identified and included in the study (5.5% [n=3806] in Kentucky and 94.5% in other states). 3028 were identified as Appalachian (1969 in Georgia and 1059 in Kentucky). Baseline characteristics were comparable between Kentucky and other states except for income and rural/urban code. Percentages of patients with an income of 70 (HR=2.83, vs 70 (HR=2.76) or 60-70 (HR=1.93), diagnosis of MM/PCL (HR=1.67), year of diagnosis 2000-2005 (HR=1.39) or 2006-2010 (HR=1.13), and income (HR=1.03 for each 5000$ decrease) persisted as significant risk factors for worse OS. Race, rural/urban code and being from non-Appalachia/Kentucky were no longer predictive of OS, while there was a non-significant trend towards worse OS for being from Appalachia/Kentucky (HR=1.07, CI=0.99-1.16, p=0.08). Conclusions Overall survival of patients with PCN in Kentucky in general, and even more prominently of patients from the Kentucky Appalachia area, is worse when compared to other states. However, when adjusted for income, this disparity corrects. This data highlights the importance of improving health outreach to this at-risk population. More studies focusing on underlying causes, such as education, compliance, co-morbidities and access to a care are warranted. Disclosures Monohan: DuPont: Other: Equity interest; Johnson & Johnson: Other: Equity interest; Novartis: Other: Equity interest; Pacria: Other: Equity interest; Pfizer: Other: Equity interest. Hildebrandt:Axim Biotechnologies: Equity Ownership; Insys Therapeutics: Equity Ownership; Pfizer: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Pharmacyclics: Research Funding; Astellas: Other: Travel; Vertex: Equity Ownership; Procter & Gamble: Equity Ownership; Abbvie: Equity Ownership; Takeda: Research Funding; Johnson & Johnson: Equity Ownership; Scotts-Miracle: Equity Ownership; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; IDEXX laboratories: Equity Ownership; Immunomedics: Equity Ownership; Endocyte: Equity Ownership; Clovis Oncology: Equity Ownership; Cellectis: Equity Ownership; Aetna: Equity Ownership; CVS Health: Equity Ownership; Celgene: Equity Ownership; Bluebird Bio: Equity Ownership; Bristol-Myers-Squibb: Equity Ownership; Kite Pharma: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other; Novartis: Equity Ownership; Juno Therapeutics: Equity Ownership; Novartis: Equity Ownership; Kite Pharma: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Sangamo: Equity Ownership; Axim Biotechnologies: Equity Ownership; crispr therapeutics: Equity Ownership; GW Pharmaceuticals: Equity Ownership; Cardinal Health: Equity Ownership; Bayer: Equity Ownership.

Introduction:High-risk hematologic malignancies are associated with significant treatment-related morbidity, particularly due to infectious events. Neutropenic fever/Febrile neutropenia (NF) is one of the most common infectious complications of chemotherapy; however, mortality rates associated with NF and the factors predictive of mortality are not well-established in the adult leukemia literature. We sought to examine factors that influence mortality and length of stay in patients admitted with NF to the inpatient hematologic malignancy service of a tertiary care center.Materials and Methods:We performed a retrospective chart review of patients admitted to our hematologic malignancy service between April 2016 and July 2018 who carried a diagnosis of NF, based upon absolute neutrophil count < 500/microL and temperature =>38.3C. We included patients who developed fever during planned admission for treatment or who were admitted for complications. Patients had primary diagnoses of AML, ALL, CML, CLL, and MDS. Patients undergoing autologous or allogenic stem cell transplant were excluded. Our analysis included demographics, primary diagnosis, primary disease status (remission, relapse, refractory), line of therapy prior to admission, duration of neutropenia, and nutritional status. We included infection-specific factors such as the presence of bacteremia, identification of an infection source, gram stain of bacteria isolated, resistance patterns, and need for ICU care. We used linear regression analysis to evaluate potential predictors of length of stay and mortality. Statistical analyses were performed with SAS.Results:We identified 100 episodes of NF that occurred in 63 patients. Median age was 58. Malignancies with the highest representation among NF episodes were AML (69%), ALL (24%), CML (3%), and CLL (2%). Infection sources were identified in 62% of episodes, with bacteremia identified in 54% of cases, accounting for 87% of sources. Mean length of stay was 18.7 (+/- 2.3 days). 14 deaths occurred, with 13 (93%) being AML patients and 11 (79%) having bacteremia. Factors associated with mortality were recurrent or relapsed disease status (RR 3.05, p = 0.034), bacteremia (RR 3.1, p = 0.047), and need for ICU-level care as defined by intubation or pressor requirements (RR 8.2, p Disclosures No relevant conflicts of interest to declare.

Patients with severe congenital neutropenia (SCN) have a markedly increased risk of developing myelodysplasia (MDS) or acute myeloid leukemia (AML). Though the genetic basis for this increased susceptibility is unknown, gain-of-function mutations of the G-CSF receptor (G-CSFR) have been found in the great majority of patients with SCN who develop MDS/AML. These mutations are somatic and produce a truncated G-CSFR that, though remaining ligand-dependent, transmits a hyperproliferative signal. We and others have shown that targeted transgenic mice expressing a representative G-CSFR mutation (d715) have markedly exaggerated neutrophil responses to G-CSF treatment. Based on these observations, it has been suggested that these gain-of-function G-CSFR mutations contribute to leukemogenesis. However, direct evidence supporting this hypothesis is scant. Moreover, it is unclear how hematopoietic cells expressing the mutant G-CSFR gain clonal dominance. We previously showed that expression of the d715 G-CSFR results in a strong competitive advantage at the hematopoietic stem cell (HSC) level, but only in the presence of an increased concentration of G-CSF. Herein, we describe studies to characterize the cellular and molecular mechanisms responsible for the clonal dominance of HSC expressing the d715 G-CSFR. At baseline, the percentage of cycling c-Kit+ lineage− Sca+ (KLS) cells was similar in WT (8.9±2.0%) and d715 G-CSFR mice (10±3.0%). However, 24 hours after a single injection of G-CSF, a significantly greater percentage of cycling KLS was observed in d715 G-CSFR compared with WT mice (34.4±2.4% versus 20±3.8%; p < .05). We next harvested KLS cells from WT or d715 G-CSFR mice 3 hours after treatment with a single injection of G-CSF or saline alone and performed RNA expression profiling. 14 genes were identified that were consistently differentially regulated by G-CSF in d715 G-CSFR versus WT KLS cells. A striking features shared by most of these genes is their regulation by STAT3 or STAT5. These data suggested the hypothesis that activation of STAT3 and/or STAT5 transduces the signal leading to HSC clonal dominance. To test this hypothesis, we first directly measured STAT activation by G-CSF in KLS cells using a flow cytometry-based method. These data showed that STAT3 and to a lesser extent STAT5 are activated by G-CSF in WT KLS cells. d715 G-CSFR KLS cells displayed significantly increased STAT5 activation by G-CSF, but STAT3 activation was slightly decreased, suggesting that STAT5 may play a key role in HSC activity. To further test this hypothesis, mice carrying a targeted mutation of their G-CSFR in which the sole remaining tyrosine in d715 G-CSFR is mutated to phenylalanine (termed d715F) were analyzed. Importantly, G-CSF induced STAT3 and STAT5 in KLS cells from d715F mice was markedly attenuated. Competitive repopulation experiments showed that the d715F G-CSFR did not confer a clonal advantage and may, in fact, confer a competitive disadvantage. Collectively, these data suggest that the d715 G-CSFR confers a clonal advantage at the HSC level that may be mediated by accentuated STAT5 activation.

This report summarizes information obtained on four generations of a kindred afflicted with a mild hemorrhagic diathesis. Studies carried out on a family of eight members and platelet counts obtained on fifty-one additional members demonstrated only mild thrombocytopenia in eleven members of three generations. The thrombocytopenia appears to be inherited as an autosomal dominant trait.

1. A fourth case of the syndrome of congenital hemolytic anemia with abnormal pigment metabolism and red cell inclusion bodies following splenectomy is described. 2. In this case an abnormality was found on paper and starch electrophoresis of the red cell hemolysate at pH 8.6. A similar abnormality has not been reported previously. 3. An increased rate of erythrocyte autohemolysis was found during in vitro incubation, Partial correction of this defect occurred in the presence of glucose or purine ribosides. 4. Genetic transmission of the defect could not be demonstrated.

1. The observations made during the administration of 114 courses of busulfan to 30 patients over a period of seven years are recorded. The responses to initial courses of therapy corresponded with those reported previously. With repeated courses of therapy, subjective improvement, the decline in the number of leukocytes, decrease of anemia and the subsidence of physical signs of the disease were as satisfactory as during the first course but tended to appear later. Patients were ambulatory and most were symptomatically and objectively improved during and after repeated courses as compared to their status beforehand. 2. Remissions were longest when the leukocyte values were 10,000 per cu. mm., or less, at the time busulfan was discontinued. Among such patients, remissions of six months or longer were seen in 85 per cent after the initial course of busulfan but in only 19 per cent after fifth or later courses. 3. Evidence of partial resistance to busulfan was seen in some cases after multiple courses of treatment. Complete resistance occurred in 15 patients upon development of the acute, myeloblastic phase of chronic myelocytic leukemia. When busulfan failed, 6-mercaptopurine and colcemide were temporarily of value; x-ray was not of benefit. After the onset of the acute phase. the median survival was three months. This mode of termination is probably no more frequent (50 per cent of cases) since the advent of busulfan therapy than before. 4. If anemia was not relieved, or a large spleen was not reduced 50 per cent in size following a course of therapy, the prognosis was poor and the acute phase imminent. 5. Thrombocytopenia in early, untreated cases was not necessarily a bad sign, nor was the use of busulfan precluded because of it. However, when thrombocytopenia appeared in a previously treated patient, without other evidence indicating busulfan toxicity, or when it occurred in a patient with three or more years of known disease, it usually presaged the development of the terminal acute phase. 6. Side effects of busulfan were significant in only one patient; this man received 8 milligrams daily, double the usual dose, for eight months and developed glossitis, anhydrosis and alopecia totalis. The major hazard in the use of the drug was the occurrence of pancytopenia. This could be related to excessive dosage. 7. Morbidity was clearly decreased. Longevity (median 42 months) was greater than in Minot’s untreated cases (median 31 months) and at least as great as that achieved by treatment with radioactive phosphorus and x-ray (median 32-41 months). Repeated courses of busulfan are considered to offer an effective and practical palliative form of therapy for chronic myclocytic leukemia, up to the time of appearance of the terminal acute myeloblastic phase.

The longevity, reckoned from the symptomatic onset of acute leukemia as well as from the initiation of treatment, of a group of 89 cases including children and adults, treated in this clinic since March, 1954, was found to exceed that of a similar group of 78 patients treated in preceding years in the same clinic. The median survival of all cases considered as a unit was increased from three to six months, as measured from the date treatment was begun. The change was found to be statistically significant as well as clinically important. The longer survival found in the 1954-57 series correlated with the greater use of three, rather than only two, chemotherapeutic agents. On analysis, improved survival was statistically proven only for individuals with lymphoblastic leukemia; for these, the median survival was 10 months after the symptomatic onset of leukemia and 7½ months after the start of treatment. Within this group, there was an even greater improvement for those whose leukocyte values immediately prior to the initiation of therapy were less than 10,000 per cu.mm.; half of these patients lived more than 12 months after treatment was begun. The reason for the exceptional longevity of patients with the lower pre-treatment leukocyte values is unknown. It appears that one can attribute at least part of the improvement to therapy. The type of statistical analysis used presents the minimum figures for improvement in median survival. When the ultimate longevity is known for the 17 per cent of the cases surviving at the closing date of the study an additional small increment may be found. The relative inefficacy of chemotherapy in myeloblastic leukemia should be a signal for greater screening of new agents in this type of tumor.

A technic for the in vitro labeling of human platelets with DFP32 is presented, critically evaluated, and compared to in vivo methods employing DFP32 and to in vitro methods using Cr51. The initial recovery of platelets labeled in vitro with DFP32 averaged 79 per cent, but the survival curve was characterized by an irreversible initial loss of platelet radioactivity. Experiments in which platelets were simultaneously labeled in vitro with both DFP32 and Cr51 suggest that this is not due to elution of DFP32. The survival curve of platelets labeled in vivo with DFP32 shows an initial transient reduction in platelet radioactivity. It is suggested that both of these aberrations in initial survival are the result of platelet injury by DFP32. Significant "tailing" was observed in the survival curves obtained with DFP32, and possible explanations of this phenomenon are discussed. DFP32-labeled platelets circulating after 5 hours apparently survive normally and disappear from the circulation as a rectilinear function over the next 6-8 days. Although both in vitro and in vivo labeling methods employing DFP32 provide a meaningful approximation of platelet lifespan, the initial and terminal aberrations of the survival curves greatly complicate further interpretation. Dextran had no detectable effect on platelet survival, and epinephrine, Mecholyl, and cutaneous vasodilatation did not alter the platelet count or the specific activity of circulating labeling platelets in human subjects. The problem of initial platelet survival and the question of an extravascular or marginal platelet pool is discussed in the light of these data.

1. A total of 108 erythrocyte protoporphyrin determinations has been made in 66 normal individuals. The geometric mean ± standard error of the mean was 31 (26-38). 2. A total of 196 determinations of plasma iron in 92 normal individuals was made. The mean ± standard error of the mean was 104.7 ± 3.4 µg per cent. 3. In a total of 150 determinations of plasma copper in 105 normal individuals, the mean ± standard error of the mean was 118.6 ± 1.2. µg per cent. 4. No significant difference in plasma iron was noted between the sexes but in females the plasma copper was significantly higher and the erythrocyte protoporphyrin slightly higher than in males. 5. Erythrocyte protoporphyrin, plasma iron, and plasma copper determinations have been made in over 112 patients with a variety of clinical conditions associated with anemia. In general, it was found that in pernicious anemia in relapse the erythrocyte protoporphyrin values were normal, the plasma iron normal or high and the plasma copper usually normal. Anemia due to iron deficiency as well as the anemia of infection were accompanied by high values for erythrocyte protoporphyrin, hypoferremia and hypcrcupremia. In nephritis with anemia the erythrocyte protoporphyrin was generally increased, the plasma iron low or normal and the plasma copper increased. Anemia associated with lymph node disorders or leukemia was accompanied by a normal or high EP, a low or normal plasma iron and an increase in plasma copper. Thalassemia major was found to be accompanied by both hypercupremia and hyperferremia; in thalassemia minor the serum iron values were normal although hypercupremia was found. Hyperferremia was noted in aplastic anemia. In cases of plumbism the erythrocyte protoporphyrin was markedly increased. Hypocupremia was noted only twice, in one patient with severe nephritis and hypoalbuminemia and in one patient with hemochromatosis. ACKNOWLEDGMENTS For samples of plasma from patients with thalassemia we are indebted to Drs. W. N. Valentine, Rochester, N. Y., P. Sturgeon, Los Angeles, and L. K. Diamond, Boston. The following gave valuable technical assistance: Misses Mary Iles, Betty Tatting and Wanda Worth.

1. A deficiency of pteroylglutamic acid has been produced in 32 swine fed a purified diet containing casein and supplemented with seven B vitamins, sulfasuxidine and a folic acid antagonist. The casein was fed at two levels, 10 and 26 per cent. Two types of casein were used: a crude preparation possessing significant "extrinsic factor" activity and a purified casein with little activity. 2. The hematologic manifestations observed were (a) severe macrocytic anemia, (b) leukopenia, due to a proportionately greater reduction in polymorphonuclear than in mononuclear cells, (3) slight thrombocytopenia, and (4) hyperplastic bone marrow with an increase in immature nucleated red cells which resemble the megaloblasts seen in the bone marrow of patients with pernicious anemia. 3. The feeding of a 26 per cent rather than a 10 per cent crude casein diet did not prevent but did delay the onset of the blood changes. Anemia developed most rapidly in the animals receiving 10 per cent purified casein. 4. The group receiving 26 per cent casein developed a greater degree of macrocytosis in the same period of time than did the group receiving 10 per cent casein. In all groups the degree of macrocytosis increased as the duration of the anemia increased. 5. The hematologic manifestations were not delayed nor was their development prevented by the intramuscular administration of 15 U.S.P. units of liver extract every 15 days. 6. The blood and bone marrow returned rapidly to normal following the administration of pteroylglutamic acid, pteroyldiglutamic acid, pteroyltriglutamic and pteroylheptaglutamic acid. Thymine and xanthopterin had little or no activity. Tyrosine, adenine and uracil were inactive. 7. Purified liver extracts and crystalline vitamin B12 were found to possess some hemopoietic activity in several animals but the activity was considerably less than that of the pteroylglutamic acid compounds. 8. The urinary excretion of "tyrosyl" (hydroxphenyl compounds) was not abnormal in the pteroylglutamic acid deficient pigs and was not altered by either pteroylglutamic acid or liver extract therapy. 9. The urinary excretion of allantoin and uric acid did not differ significantly from the normal. Immediately following therapy with pteroylglutamic acid, however, in association with the reticulocytosis and lasting for the same period, there was a marked increase in the excretion of allantoin. 10. The results suggest that both pteroylglutamic acid and a factor in liver extract similar to or identical with vitamin B12 are required for normal hemopoiesis in the pig. ACKNOWLEDGEMENTS The crude methylfolic acid antagonist, xanthopterin, and the pteroylglutamic acid compounds, with the exception of pteroylheptaglutamic acid, were kindly furnished by the Lederle Laboratories, Pearl River, New York, through the courtesy of Dr. T. H. Jukes and Dr. S. M. Hardy. Sulfasuxidine was generously furnished by Sharp & Dohme, Inc., Philadelphia, Pa., through the courtesy of Dr. W. A. Feirer. Pteroylheptaglutamic acid and Natola were supplied by Parke, Davis & Company, Detroit, Mich., through the courtesy of Dr. A. E. Sharp and Dr. J. J. Pfiffner. Biotin was obtained from Hoffmann-LaRoche, Inc., Nutley, N. J., through the courtesy of Dr. E. L. Sevringhaus. The vitamins, with the exception of pteroylglutamic acid and biotin and including vitamin B12 were kindly furnished by Merck and Company, Inc., Rahway, N. J., through the courtesy of Dr. A. Gibson and the late Dr. D. F. Robertson. Experimental liver extracts (No. 1124, 1063, 1066 and 1067) were generously furnished by Armour and Company, Chicago, Illinois through the courtesy of Dr. E. E. Hays. We are indebted to Mrs. Darlene Kehl, Mr. George Trappett, and Mr. Ocie Hadley for technical assistance.

A simple, easily constructed apparatus for electroplating radioactive iron has been described by which certain disadvantages of other forms of apparatus have been eliminated. Sixteen samples can be plated each day without difficulty. The technic employed for preparing the radioactive iron for electroplating has been given. The writers are indebted to Dr. P. F. Hahn and his staff who permitted one of them (M. L.) to spend several weeks in the Biochemical Laboratory at the Vanderbilt University School of Medicine and generously gave invaluable instruction and advice.

1. Thirteen cases of plasma thromboplastin component (PTC) deficiency or Christmas disease are reviewed and summarized. Of these cases, only in one were the whole blood coagulation time and prothrombin consumption normal. 2. Two cases of a mild bleeding disorder, occurring in brothers with slightly prolonged whole blood coagulation times and normal prothrombin consumption are described. 3. In these two cases, the thromboplastin generation test revealed the deficiency of a serum factor essential for normal thromboplastin generation. A mild deficiency of PTC was demonstrated by the correction of the serum deficiency by the addition to the patients’ serum of a partially purified preparation of PTC. 4. The differentiation of PTC deficiency from hemophilia is discussed. 5. Mild bleeding disorders due to a moderate reduction of antihemophilic globulin (AHG) or PTC can be differentiated by the use of the thromboplastin generation test.

A total of 20 swine were fed a diet adequate in all known respects except that soybean protein was substituted for casein, succinylsulfathiazole and a folic acid antagonist were added, and vitamin B12 and pteroylglutamic acid were withheld from the vitamin supplement. The animals developed macrocytic anemia, leukopenia and neutropenia, accompanied by erythroid hyperplasia of the bone marrow. Tue erythroblasts consisted mainly of immature macronormoblasts but a few atypical megaloblasts were also observed. The anemia responded rapidly and completely to the administration of both vitamin B12 and pteroylglutamic acid. The administration of pteroylglutamic acid alone resulted in an immediate return of the blood and bone marrow to within normal limits but after several months there was a partial hematologic relapse in spite of continued therapy with this vitamin. The administration of vitamin B12 alone resulted in only partial remission of the anemia and the bone marrow remained macronormoblastic although the megaloblasts tended to disappear. Growth of the animals was stimulated by the administration of either vitamin but the administration of both vitamins simultanseously resulted in the greatest rate of growth. No manifestations of neurologic disturbances or of inscreased pigment excretion were observed in the deficient swine.

The effect of a single injection of vinblastine sulfate was studied in 50 mongrel dogs. Nine of 34 dogs given 0.2 mg./Kg. of VLB died with gastrointestinal toxicity and the mortality rate increased as the dosage of VLB was increased. The morphologic pattern of leukocyte suppression and recovery in the bone marrow and blood was studied in detail in surviving animals. The cells of the bone marrow were markedly affected by VLB. Within 4 hours there was an increase in the number of cells in metaphase and, by day 1, virtually all proliferating leukocytes and erythrocytes had disappeared. An orderly repopulation of the bone marrow followed. The neutrophils, eosinophils, lymphocytes and monocytes of the blood were all markedly altered in concentration after VLB. Each type of cell first decreased to abnormally small numbers and then increased to abnormally large numbers in the blood. The curve of disappearance from and reappearance in the blood differed for each cell type. The changes in blood neutrophil number and morphology were correlated with changes in the blood neutrophil precursor cells of the marrow. The following conclusions were reached concerning the neutrophils and the assumptions implicit to these conclusions were detailed. 1. In the dog, the marrow contains enough post-mitotic granulocytes to replace those lost from the blood for at least 3 to 4 days. 2. The release of mature neutrophils from the bone marrow is a function of the rate at which blood neutrophils are lost and proceeds normally even when the marrow granulocyte reserve is partially depleted.

Present knowledge concerning the kinetics of granulopoiesis has been reviewed and quantitative data concerning granulokinetics in normal human subjects are presented. A. When granulocytes are labeled in vitro and returned to the circulation of the donor, the distribution of the cells in the circulation and the rate of disappearance of the cells from the circulation can be measured. 1. The total blood granulocyte pool (TBGP) consists of two compartments which are in equilibrium with each other. These pools have been designated the circulating granulocyte pool (CGP) and the marginal granulocyte pool (MGP). The size of the pools has been measured in 109 normal male subjects. The mean values, expressed as numbers of cells x 107 per Kg. of body weight were as follows: TBGP, 70; CGP, 31; and MGP, 39. The mean ratio of the CGP to the TBGP was 0.44. 2. The labeled granulocytes leave the TBGP in an exponential fashion with a mean half-time disappearance (T½) of 6.7 hours as determined in 56 normal male subjects. No evidence has been obtained for a return of granulocytes to the blood. 3. The mean value for the granulocyte turnover rate (GTR) in 56 normal male subjects was 163 x 107 granulocytes per Kg. of body weight per day. Thus, the TBGP turns over 2.3 times per day and the turnover time for the TBGP is 10.4 hours. B. When granulocytes are labeled in vivo by the intravenous administration of DFP32, the rate of disappearance of granulocytes from the circulation and the time required for myelocytes to divide, mature and appear in the blood can be measured. In addition, the generation time of myelocytes can be approximated. From the time parameters and the GTR, the bone marrow pool sizes and turnover times can be calculated. These determinations and calculations have been made for a group of 21 normal male subjects. 1. The mean half-time disappearance (T½) of in vivo labeled granulocytes from the circulation was 7.2 hours. This value agrees well with the value of 6.7 hours obtained after the in vitro labeling of granulocytes. 2. The mean time required for myelocytes to divide, mature and appear in the blood was 11.4 days. 3. The mean generation time of myelocytes was estimated to be not more than 2.9 days. 4. The total granulocyte pool in the bone marrow (neutrophilic myelocytes, neutrophilic metamyelocytes and PMN neutrophils) was calculated to be 186 x 108 cells per Kg. of body weight with a mean turnover time of 11.4 days. The myelocyte pool was estimated to be 41 x 108 cells per Kg. with a turnover time of 2.5 days; the metamyelocyte pool consisted of about 76 x 108 cells per Kg. with a turnover time of 4.7 days; the average size of the mature marrow PMN neutrophil pool was 69 x 108 cells per Kg. of body weight with a turnover time of 4.2 days. C. A kinetic model for granulopoiesis, based on the studies with the DFP32 label, is presented. In this model, myelocytes are depicted as approaching a self-perpetuating population of cells. Some cells enter this population from populations which are less mature but this latter source of cells is small under conditions of normal steady state kinetics. One of the daughter cells of a myelocyte division remains in the myelocyte population to divide again. The other daughter cell enters the metamyelocyte population. The metamyelocyte and PMN neutrophil population is incapable of division and cells move through this population in sequential fashion in the process of maturation. The cells then enter the blood where they equilibrate rapidly between the two blood compartments. The cells are removed from the total granulocyte pool in a random fashion. There is no appreciable pool of granulocytes in the extramedullary tissues of normal subjects and granulocytes do not return from the tissues to the blood. The entire movement of granulocytes from marrow to tissues is uni-directional.

1. Erythrocyte hemins, extracted with acid-acetone, exhibited multiple components on two chromatographic systems. However, this heterogeneity can be explained by various physicochemical properties of hemin in solution and does not imply that heme, when attached to globin in the native hemoglobin molecule, is heterogeneous. 2. The presence of a non-polar fraction may be accounted for by esterification of protohemin as a result of reaction with small amounts of methanol contaminating the acetone and/or the presence of some un-ionized protohemin molecule in solutions of low pH. 3. The presence of poorly soluble fractions is probably the result of polymerization of the hydroxyhemin molecule into so-called β- and γ-hematins. 4. The formation of mesohemin is considered unlikely, but the formation of deuterohemin or hematohemin cannot be excluded. 5. No changes in hemin chromatographic patterns were noted in disease. 6. It is necessary to evaluate reports concerning chromatographic hemin heterogeneity in the light of the artifacts described above before attributing physiologic or pathogenetic significance to the findings.

1. A method, based on the uptake of radioiron into heme, is described for the measurement of heme synthesis in a hemolysate of chicken erythrocytes. 2. The addition of glycine, δ-aminolevulinic acid, porphobilinogen or protoporphyrin 9 to the system augmented heme synthesis. 3. Citrate potentiated heme synthesis in the presence of glycine, but had no effect when porphobilinogen was added. Succinate, in the presence of glycine did not enhance heme synthesis. 4. The addition of coproporphyrin I or III, or uroporphyrin I or III, did not augnment the uptake of radioiron into heme. The addition of mesoporphyrin 9 or hematoporphyrin 9 enhanced the uptake of radioiron. These studies are iterpreted as suggesting that protoporphyrin, but not uroporphyrin or coproporphyrin, is a precursor of heme. For reasons discussed, further work will be necessary to determine if mesoporphyrin and hematoporphyrin are precursors of protoheme. 5. The synthesis of heme was inhibited by the addition of malonate or lead. Evidence is presented that both of these substances affected heme synthesis at several different levels, particularly the formation of δ-aminolevulinic acid and the incorporation of iron into protoporphyrin. 6. Plasma extracts from chickens, made anemic by bleeding or by the administration of phenylhydrazine, did not potentiate heme synthesis. 7. Normal, nonreticulated, human erythrocytes failed to synthesize heme in the presence of glycine, δ-aminolevulinic acid, porphobilinogen on protoporphyrin 9.

1. The urinary excretion of uric acid was studied in 17 normal subjects and in 38 patients with leukemia. The mean excretion of uric acid by the normal subjects was 6.5 mg./Kg. of body weight /24 hrs. The mean excretion of uric acid in 14 patients with acute lymphoblastic leukemia was 30.3 mg./Kg. /24 hrs.; in 13 patients with acute myeloblastic leukemia, 13.0 mg.; in 6 patients with chronic lymphocytic leukemia, 5.2 mg.; and in 5 patients with chronic myelocytic leukemia, 13.5 mg. 2. Following therapy with cortisone, 6-mercaptopurine or Amethopterin, the urinary excretion of uric acid increased in the cases of acute leukemia as the leukocyte count declined. As the leukocyte count approached normal levels, the uric acid excretion decreased. The urinary excretion of xanthine and guanine paralleled the excretion of uric acid. 3. In association with the administration of an aromatic nitrogen mustard derivative to one patient with chronic lymphocytic leukemia and Myleran to one patient with chronic myelocytic leukemia, there was only a slight increase in uric acid excretion.

1. A method has been presented by which granulocytes can be labeled in vivo with diisopropylfluorophosphate containing radioactive phosphorus. The leukocytes are isolated from blood by dextran sedimentation of erythrocytes and are then treated with gramicidin and lysolecithin to remove remaining red cells. Platelets are removed by differential centrifugation. The isolated leukocytes are placed between two squares of scintillating plastic and counted with a scintillation counter. 2. Leukocytes essentially free of erythrocytes and platelets can be obtained by the method outlined. The efficiency of the plastic scintillation counting method for radioactive phosphorus is about 74 per cent and leukocyte samples obtained from 20 ml. samples of normal blood can be counted with a reproducibility of ±10 per cent. 3. The administration of 2 mg. of diisopropylfluorophosphate either intramuscularly or intravenously is without significant toxic side effects. 4. No evidence has been obtained that the label damages the leukocytes. 5. No evidence has been obtained that the label elutes from leukocytes under the conditions of these studies. 6. Diisopropylfluorophosphate labels granulocytes for a brief period of time following injection. The label is not reutilized after death of the cells.

1. Two patients with microcytic hypochromic anemia, hyperferremia, and hemosiderosis have been described .A partial hematologic remission was observed in both patients following the administration of pyridoxine. 2. Interruption of pyridoxine therapy resulted in reticulocytopenia, a decline in the concentration of hemoglobin and a decrease in free erythrocyte protoporphyrin. Increased excretion of kynurenine and kynurenic acid, but not xanthurenic acid, was observed in the urine of one of the patients following administration of tryptophane. The excretion of tryptophane metabolites was within normal limits in the second patient. 3. Reinstitution of pyridoxine therapy was followed by reticulocytosis, an increase in free erythrocyte protoporphyrin and an increase in the concentration of hemoglobin. The excretion of tryptophane metabolites in the urine following the administration of tryptophane was within normal limits in both patients. However, microcytosis, hypochromia, anemia and hyperferremia persisted. 4. The administration of brewer’s yeast, Valentine’s liver extract, calcium disodium ethylenediamine tetra-acetic acid, ethinyl estradiol, pantothenic acid, pyridoxal, pyridoxamine, ascorbic acid, niacin, riboflavin, glutamic acid and tryptophane failed to elicit a further hematologic response. 5. These patients have been compared with the seven other reported cases of "pyridoxine-responsive" anemia.

1. Two morphologically distinct populations of erythrocytes were found in a mother and in two of her daughters, one of whom (the proband) was anemic. One erythrocyte population was morphologically normal; the other was hypochromic and microcytic. 2. The X-linked blood group antigen, Xga, was present in erythrocytes from the mother and the two daughters, but not in erythrocytes from the father. The daughters were, therefore, heterozygous for the gene controlling this antigen. 3. Separation of the two populations of erythrocytes was accomplished by centrifugation in layered gum acacia solutions of different specific gravity. 4. The microcytic cells from the three affected individuals were Xga-positive. Isolated normal cells were Xga-positive in the mother, but negative in both daughters. These data suggest that the erythrocyte defect is X-linked and that the phenomenon of X-inactivation applies to genes controlling both the morphologic defect and the Xga antigen. 5. The free protoporphyrin content of the isolated microcytes was lower than that of the normal cells. The capacity of the microcytes to convert delta-aminolevulinic acid to protoporphyrin was unimpaired. On these bases it is suggested that the hereditary defect lies either at or before the step in which delta-aminolevulinic acid is synthesized.

A 26 year old American housewife of Sardinian extraction with chronic hypochromic anemia was found to have a hemoglobin component identical to hemoglobin H. The A2 hemoglobin fraction was decreased. Relatives were found to exhibit the hematologic features of thalassemia trait. In this pedigree, in contrast to the usual finding in the "thalassemia trait," the A2 values were not increased. The same observation had been made in the only other comparable report.

1. Additional evidence has been presented that the formation of heme in vitro from iron and protoporphyrin is enzyme dependent. 2. An enzyme solution was prepared from the active particulate matter of a chicken erythrocyte hemolysate. The enzyme is soluble in 0.15 M KCl and optimally active at pH 7.9. 3. The rate of heme synthesis was constant over the first 30 minutes and approached maximal values at 3 to 4 hours. At optimal concentrations of protoporphyrin and iron the rate of heme synthesis over the first 30 minutes was proportional to enzyme concentration. 4. The enzyme solution was 89 per cent inactivated after heating at 56 C. for 30 minutes. Optimal stability for 3 hours was at pH 7.4. It was unstable when lyophilized or on storage at 5 C. or -30 C. 5. The enzyme was inhibited by 1 x 10-2 M p-chloromercuriphenylsulfonate and 1 x 10-2 M iodoacetamide. 6. There was a 70 per cent loss of activity after dialysis of the enzyme solution for 22 hours against water. The dialyzed enzyme solution was reactivated with either reduced glutathione or cysteine. 7. The enzyme solution augmented heme synthesis in vitro from δ-amino-levulinic acid, porphobilinogen and protoporphyrin, but not from glycine.

The intraperitoneal administration of methyl cellulose into rats over a period of fifteen weeks resulted in the development of a syndrome characterized by massive splenomegaly, hyperplasia of the bone marrow elements, normocytic, normochromic anemia, reticulocytosis, leukopenia, a mild thrombocytopenia in 9 of the 10 animals, ascites, and infiltration of the spleen, liver and kidneys with "storage-cell" macrophages. The administration of methyl cellulose to rats previously splenectomized produced similar histologic lesions but failed to produce the hematologic abnormalities. It is suggested that the syndrome produced by methyl cellulose may represent an experimental form of the process to which, in man, the term "secondary hypersplenism" has been applied.

Three-hundred and ninety-nine patients with acute leukemia examined during the period 1947-1964 were divided into three sequential series and their survival, from diagnosis to death, was compared. A statistically significant increase in duration of survival for myeloblastic leukemia from a median of 2 to 5 months occurred between series I and series III. This is the first convincing evidence that 6-mercaptopurine therapy influences survival in myeloblastic leukemia. A steady increase in median survival of patients with lymphoblastic leukemia from 4 to 8 to 12 months was found in the three series. The results of analysis of these series are compared to other reported series. The hypothesis —that the longer survivals reported for patients treated in hematology clinics compared to that of patients selected from population areas reflects patient selection—was examined and appeared unlikely.

1. A total of 70 swine were fed a diet consisting only of evaporated cow’s milk. Copper and iron were added to the diet of 10 of the pigs. Iron only was added to the diet of 46 of the pigs. Copper only was added to the diet of 10 of the pigs. Four pigs received neither iron or copper. 2. The animals deficient in copper developed skeletal abnormalities, microcytic hypochromic anemia, leukopenia, neutropenia, normoblastic hyperplasia of the bone marrow, hypoferremia, an increase in the iron-binding capacity of the plasma, hypocupremia and reduced erythrocyte copper as well as tissue copper. No abnormality in porphyrin metabolism was observed and tissue as well as erythrocyte catalase activity was not significantly reduced. Following the administration of copper, the blood of the animals was rapidly and completely restored to normal. 3. The animals deficient in iron developed a severe microcytic, hypochromic anemia, normoblastic hyperplasia of the bone marrow, hypoferremia and an increase in the total iron-binding capacity of the plasma. No abnormality in copper or porphyrin metabolism was observed in these animals except for a slight elevation in the plasma copper level and a marked increase in liver copper. 4. The animals deficient in both copper and iron developed all of the manifestations noted in the copper-deficient pigs. These changes occurred more rapidly and to a greater degree than in the swine with a deficiency of either element alone. 5. The morphologic and biochemical similarities between anemia due to copper deficiency and anemia due to iron deficiency suggest that in copper-deficient swine there is an abnormality in the metabolism of iron and that, furthermore, the anemia may be the consequence of this abnormality.

In an effort to produce a deficiency of vitamin B12 a total of 70 pigs were fed a purified diet containing soybean alpha protein in place of casein. One group of animals was started on the diet at 2 to 7 days of age. A second group began at 21 to 28 days of age. Methionine, iodinate casein, desiccated thyroid and pteroylglutamic acid were added to the diet of certain animals and! omitted from the diet of other pigs. In addition, 9 pigs were gastrectomized. Forty-three of the animals survived for a sufficiently long period of time for adequate evaluation of the results of the experiment. Severe liver damage was observed in 24 of the 25 animals autopsied. The only animal not showing liver damage received vitamin B12 from the beginning of the experiment. Necrosis of the liver cells, fatty infiltration, or both, occurred in the presence of a high fat diet containing apparently adequate amounts of protein, choline, vitamin E and methionine. These pathologic changes were apparently prevented but not reversed by the administration of vitamin B12. Growth of the animals on the above diets without added vitamin B12 was retarded as compared with the growth of animals on the same diet supplemented with this vitamin. The administration of vitamin B12 to the deficient animals resulted in rapid growth. Of the 39 animals not receiving vitamin B12 13 failed to develop anemia, 16 developed a mild anemia and in 10 a moderately severe anemia was present. When present the anemia was normocytic and in 24 pigs was accompanied by a moderately severe neutropenia. Differential cell counts on the sternal marrow were normal except for a slight increase in the proportion of normoblasts. These hematologic alterations were neither consistently or completely corrected by the administration of vitamin B12 in spite of the fact that definite and sometimes marked reticulocyte increases followed. When methionine deficiency was associated with vitamin B12 deficiency, anemia appeared to be more severe. The administration of aureomycin, an "animal protein factor," did not stimulate growth and failed to induce a hemopoietic response. There was no macrocytic anemia, the bone marrow was not megaloblastic, and neurologic disturbances or morphologic alterations in the neutrophils were not observed. These results are in contrast to those obtained in pigs with an experimentally produced deficiency of pteroylglutamic acid. Such animals develop macrocytic anemia, leukopenia and a macronormoblastic type of bone marrow. It is not possible to give with any assurance the reason why megaloblastic anemia was not produced in the "B12-deficient" animals. This may have been due to the fact that (1) the deficiency was not sufficiently severe to result in such a change in the hemopoietic system; or (2) because pteroylglutamic acid prevents the development of megaloblastic anemia even in the absence of vitamin B12.

1. Following splenectomy in the albino rat, the total leukocyte count increased approximately 100 per cent in seven days, and remained significantly elevated for seventy to ninety days, after which time time leukocytes returned to normal levels. This increase in circulating leukocytes was due to an increase in both neutrophils and mononuclear cells. Partial omentectomy and unilateral nephrectomy produced increases of less magnitude and much shorter duration than those which followed splenectomy. 2. Removal of as much as 75 per cent of the spleen resulted in a leukocyte increase resembling in magnitude and duration that of control operations. 3. When small portions (less than 10 per cent) of the spleen were transplanted to other sites, the leukocyte response also resembled that which followed the control operations. 4. When splenectomy was performed in one partner of parabiotic rats, no rise occurred in the leukocyte count of either animal. When the spleen of the second partner was then removed, a rise in the leukocyte count of both animals occurred. 5. When rats were made leukopenic by pteroylglutamic acid deficiency, no rise in the leukocytes in the peripheral blood occurred following splenectomy. 6. It is concluded that in the rat the spleen exerts an influence on the level of circulating leukocytes, and that the results of these experiments support but do not conclusively prove the hypothesis that this organ exerts this influence by controlling the rate of production and/or liberation of leukocytes in the bone marrow. These studies do not exclude the possibility that under certain circumstances the spleen may destroy white cells.

1. The morphology of the erythrocytes has been studied in 22 normal swine, 65 swine deficient in copper, and 16 swine deficient in iron. The mean values (± the standard deviation) for the volumes of packed red cells in the three groups were 42 ± 2.5, 21 ± 6.6, and 21 ± 6.1 ml/100 ml., respectively. The mean values for the mean corpuscular volumes were 55 ± 3.1, 43 ± 7.1, and 36 ± 5.3, respectively. The mean values for the mean corpuscular hemoglobin concentrations were 33 ± 1.1, 29 ± 2.3, and 28 ± 3.0, respectively. 2. The addition of 11 water-soluble B vitamins, 4 fat-soluble vitamins, ascorbic acid, and minerals (with the exception of copper) to the copper-deficient milk diet did not prevent or delay the development of anemia, modify the morphology of the red cells or alter the degree of hypoferremia. 3. The normoblasts in the marrow of a copper-deficient pig were similar morphologically to those in the marrow of a pig deficient in iron. 4. The intravenous administration of one Gm. of iron, given prior to the development of copper-deficiency, did not delay or prevent the development of anemia. 5. It is concluded that the anemia of copper-deficiency in swine is morphologically similar to the anemia due to iron deficiency in swine.

plastic in cases of anemia associated with infection,’ the anemia is refractory to therapy, being relieved only when the underlying infection is successfully eradicated. The anemia is accompanied by a profound metabolic disturbance as indicated by the finding of hypoferremia, hypercupremia, and elevated erythrocyte protoporphyrin levels.’ It is recognized, also, that infection is associated with a disturbance in protein metabolism; thus the serum albumin decreases, and increased excretion of urea in the urine has been reported.3 As part of a study of the pathogenesis of the anemia associated with inflammation, and in an attempt to find a means whereby the failure to form hemoglobin might be overcome, it was considered of interest to study the effect of cobalt. By the administration of cobalt, polycythemia can be produced in many laboratory animals.4’5 The increase in red cells and hemoglobin has been reported as being due to an actual increase in red cell mass,6’7 and an increase in reticulocytes in the blood has been observed. The mean corpuscular volume was found increased, owing mainly to greater cell thickness,7 the bone marrow becomes hyperplastic,’.9 and metaplasia occurs in the spleen, liver, and kidneys.9’10 The administration of cobalt was found to overcome the anemia produced by the toxic action of benzol in rabbits’ and that caused by protein deficiency in rats” and was even reported to relieve the physiologic and nutritional anemia of children.” Kleinberg and his associates’ found that in rabbits made anemic by the injection of 0.5 to 1.0 ml. of benzene for a period of � weeks, the daily administration of 50 ml. of cobalt nitrate overcame the anemia despite the continued administration of benzene. The marrow of the control benzene rats was fatty and aplastic, while the marrow of the rats treated with cobalt and benzene was hyperplastic. It has been shown by Dorrance et al)#{176} that the work performance of rats having cobalt polycythemia is increased under conditions of anoxia, thus indicating that the increased hemoglobin is useful for oxygen carriage.

1. The total course of acute leukemia in 55 patients managed in one clinic disclosed 149 febrile episodes. 2. Fever occurred virtually only when the leukemia was in relapse. 3. Infection was the cause of fever in 102 of the 149 episodes of fever. 4. With survival after the onset of symptoms of acute leukemia beyond the mean duration of life characteristic of that kind of acute leukemia, infection appeared to be more often the cause of fever than when survival was less than the mean for that kind of leukemia. 5. Fever due to infection could not be reliably differentiated from fever not due to infection by either the height or character of the fever curve, or by counting the absolute number of mature polymorphonuclear leukocytes in the blood. 6. Infection causing febrile episodes was most successfully detected by means of history, physical examination, chest roentgenogram, blood culture and other cultures as indicated by the preceding maneuvers. 7. Consideration of the fever of acute leukemia from the point of view of present day studies of the pathogenesis of fever did not clearly implicate known mechanisms of pyrogenesis. 8. The interplay of state of leukemia, nature of infecting microorganism and anti-infectious and antileukemic therapies is related to outcome in febrile episodes due to infections. The management of febrile episodes is discussed. 9. Increased survival time in children with acute lymphoblastic leukemia has not been accompanied by increased morbidity.