Initial WBC Research Articles

Prognostic significance of vacuoles in L1 lymphoblasts in childhood acute lymphoblastic leukaemia: a report from Children's Cancer Study Group.

From February 1975 to February 1977, 880 patients with acute lymphoblastic leukaemia were enrolled on Children's Cancer Study Group protocol 141 designed to evaluate prognostic factors and more intensive therapy for patients with poor prognosis. 765 diagnostic bone marrow aspirates from 23 institutions were available for classification using the French-American-British system. 60 of 615 patients with L1 morphology had vacuolated lymphoblasts. Patients with vacuolated lymphoblasts had a better disease-free survival (P = 0.14) and a significantly better survival (P = 0.03) but the presence of vacuoles was associated with a low initial WBC and an age range associated with improved prognosis for disease-free and over-all survival.

High risk acute lymphoblastic leukemia in Denmark

In a retrospective study of acute lymphoblasic leukemia (ALL) in Denmark from 1973 to 1981, 95/267 children below 15 years of age fulfilled at least one of the following high risk (HR) criteria: WBC > 50 × 109/1, mediastinal mass, meningeal leukemia, extramedullary leukemia, T-ALL, B-ALL and congenital leukemia. Significantly more of the children in HR had considerable hepato- and/or splenomegaly compared with children in the standard risk (SR) and intermediate risk (IR) groups. Hemoglobin values above 6.0 mmol/l were found in 35% of HR children and in 9% of children in SR and IR (p < 0.0005). Treatment protocols varied. The percentage achieving complete remission (CR) was 93.7. Median relapse free survival (RFS) was 18 months. Twenty-nine children (32.5%) have been in CCR for 24–114 months as of July 1983. Initial WBC was the only independent prognostic parameter. Of children with initial WBC < 50 × 109/l, 62% remained in CCR compared to 15% with WBC > 50 × 109/l. Treatment protocols employed before July 1977 were significantly inferior to protocols employed during the last half of the study period. Fifty-seven patients relapsed most frequently in the bone marrow. In 38.5% of the relapses, the central nervous system (CNS) was involved. When the CNS prophylaxis was initiated early during induction treatment, significantly fewer CNS recurrences arose than when the CNS prophylaxis was started after remission had been induced. Acute lymphoblastic leukemia, children, high risk, prognosis.

Testicular infiltrates in children with acute lymphoblastic leukemia: a prospective study.

The incidence of testicular infiltrates in 68 boys with acute lymphoblastic leukemia in first remission (1974-81), was prospectively investigated through careful clinical examination and routine bilateral biopsies at 2-3 years of remission. All boys were under 14 years of age and they were treated with protocols D.74 and Pethema 7/78. Seven patients (10.3%) presented an isolated testicular relapse (ITR) during the chemotherapy period. In 13 of the 43 testicular biopsies (31%) leukemic infiltrates were found, and in another two findings were controversial. Three boys, two with previous negative biopsies, had an ITR 6 to 18 months after therapy was stopped. Finally, three others had simultaneous relapses in testes and bone marrow, one during chemotherapy and two after suppression. In all, 23 patients (33.8%) in first remission had overt or occult ITR. Overall estimated incidence rate of testes leukemia is 40% in all the groups. Incidence of early and occult ITR was higher in boys with initial WBC counts over 20 X 10(9)/1. Therapy in ITR generally consisted of local radiotherapy (20-25 Gy), a new induction treatment followed by 2-year maintenance treatment; in three patients with early ITR, orchidectomy was also performed and six were given a new CNS preventive treatment. Clinical course in the seven patients with early ITR was unfavourable in five, with subsequent hematological relapses and death; one had a long-term disease-free survival (80 + months) and the other was a recent case. Ten of the 13 patients with occult infiltrates continued in remission and four were off treatment with a follow-up of over 66 months. The three patients with late ITR were in 2nd remission at 8-18 months after a new cessation of therapy. It may be concluded from this study that prognosis in ITR is related to the phase of presentation: it is unfavourable in cases of early ITR, but in occult infiltrates, detected by routine biopsy, and in late ITR combined therapy is effective in most cases.

Allogeneic bone marrow transplantation for patients with acute lymphoblastic leukemia

Fifty-two patients with acute lymphoblastic leukemia (ALL) underwent allogeneic bone marrow transplantation following cytoreduction with total body irradiation and cyclophosphamide. Twenty-two patients were in second remission, 15 in a later remission, and 15 were in relapse at the time of the transplant. At a median follow-up of 24 mo, 14 of those in second remission survive in continuous remission compared to 5 in later remission and 4 in the relapse group. Statistical analysis showed an improved disease-free survival for the second remission group (p = 0.09). Patients transplanted in later remission or relapse had a similar survival. The improved survival in second remission resulted from a decreased relapse rate posttransplant, as the early mortality from nonleukemic causes was similar among the groups (p = 0.01). In the second remission patients, no characteristics of the initial leukemia were identified that significantly affected outcome. In the combined later remission and relapse group, poor prognosis posttransplant was associated with initial WBC greater than 20K, age at diagnosis older than 10, or initial remission duration less than or equal to 1 yr. These results suggest that extended disease-free survival may be achieved by second remission transplantation and that improved therapy is necessary for later remission or relapse transplants due to the high rate of posttransplant relapse.

Allogeneic Bone Marrow Transplantation for Patients With Acute Lymphoblastic Leukemia

AbstractFifty-two patients with acute lymphoblastic leukemia (ALL) underwent allogeneic bone marrow transplantation following cytoreduction with total body irradiation and cyclophosphamide. Twenty-two patients were in second remission, 15 in a later remission, and 15 were in relapse at the time of the transplant. At a median follow-up of 24 mo, 14 of those in second remission survive in continuous remission compared to 5 in later remission and 4 in the relapse group. Statistical analysis showed an improved disease-free survival for the second remission group (p = 0.09). Patients transplanted in later remission or relapse had a similar survival. The improved survival in second remission resulted from a decreased relapse rate posttransplant, as the early mortality from nonleukemic causes was similar among the groups (p = 0.01). In the second remission patients, no characteristics of the initial leukemia were identified that significantly affected outcome. In the combined later remission and relapse group, poor prognosis posttransplant was associated with initial WBC greater than 20K, age at diagnosis older than 10, or initial remission duration less than or equal to 1 yr. These results suggest that extended disease-free survival may be achieved by second remission transplantation and that improved therapy is necessary for later remission or relapse transplants due to the high rate of posttransplant relapse.

Therapeutic leukapheresis for hyperleukocytosis in acute myelocytic leukemia.

Twenty-two patients with newly diagnosed acute myelocytic leukemia (AML) and white cell counts (WBC) greater than 100,000/microliters received one, two, or three leukaphereses prior to induction chemotherapy with cytosine arabinoside (Ara-C) and daunorubicin (DNR). Fifteen of 22 (68%) achieved a complete remission. Greater than a 30% decrease in initial WBC was found to be an important predictor of response. Fifteen of 17 patients (88%) with greater than 30% reduction of initial WBC achieved remission, while none of 5 patients with less than a 30% reduction responded (P = 0.001).

Acute lymphoblastic leukemia in children: Current status, controversies, and future perspective

Disease-free survival (DFS) in childhood ALL is 60%, and survival in good, average, and poor prognostic groups defined by initial WBC and age is 90, 60, and 45%, respectively. Additional immunological, morphological, biochemical, cytokinetic, and cytogenetic factors have been identified, illustrating the heterogeneity of ALL and its derivation from malignant clones at various stages of differentiation and with varying rates of proliferation. Of biologic importance, these factors may refine further the characteristic features of clinically-determined prognostic groups. Multivariate analysis of large prospective trials with homogeneous therapy will be required to determine the independent prognostic importance of these factors. Current treatment strategies in ALL include (1) tailoring therapy and its intensity to prognostic groups; (2) multiple-drug combinations in induction; (3) early use of intrathecal (IT) methotrexate (MTX); (4) CNS prophylaxis with IT MTX alone in good prognosis patients and combined cranial radiation (CXRT), 1800 rads plus IT MTX, in average and poor prognosis patients. Current studies show a CNS relapse rate of 5% in all prognostic groups. Late neuropsychological defects caused by cranial XRT and IT MTX have prompted programs designed to reduce the potential late toxicity of CNS prophylaxis. More pronounced in younger children, these abnormalities include decreased IQ, visual-motor incoordination, poor performance in mathematics, and memory dysfunction. Until 1980, more intensive induction, consolidation, and maintenance therapy had failed to prolong DFS in children with a poor prognosis. In West Germany (Berlin-Frankfurt-Muenster protocol) a 70 to 75% DFS is seen in all patients regardless of initial WBC, suggesting that effective therapy will override prognostic factors. Ultra-high-dose MTX, without cranial radiation, is also showing promise in poor prognosis patients. Other issues include the optimal duration of therapy, the role of testicular biopsies, and prophylactic testicular radiation. Recent studies suggest that prognostic factors lose their significance after 2 years of continuous complete remission and that 2 years of maintenance therapy is adequate. Bilateral open-wedge testicular biopsies have identified occult testicular disease in 8 to 10% of males. A unified approach to children with leukemia/lymphoma, a group with a particularly poor prognosis, utilizing NHL-type therapy may be more effective than conventional ALL therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinicopathologic characteristics of septicemia in sickle cell disease.

Bacterial septicemia occurred in 22 of 210 pediatric patients with sickle cell disease over a nine-year period, an attack rate of 10.5%. Children less than 2 1/2 years old with hemoglobin SS were at greatest risk; Streptococcus pneumoniae was the most common pathogen. Although sudden febrile illness developed in nine patients, in 13 a gradual prodrome was associated with symptoms for more than 24 hours before evaluation. Both initial body temperature and WBC count were highly variable. In all six fatal cases, autopsy disclosed adrenal hemorrhagic necrosis, which in three was diffuse and typical of that seen in the Waterhouse-Friderichsen syndrome. Recommendations in patients with sickle cell disease and fever, even if only of moderate degree, include the rapid initiation of antibiotic therapy and the use of corticosteroids at the first sign of circulatory insufficiency.

Sex differences in prognosis of childhood T-cell leukemia.

Bone marrows of 41 untreated children and adolescents with acute lymphocytic leukemia were studied by combined immunologic and histochemical methods at the time of diagnosis. Eleven were classified as T-cell lymphoblastic leukemias (27%) on the basis of cytochemical stains and E-rosette assay. The patients in this group has low median age of 8 years, relatively low median WBC of 13.4 x 10(3)/cc, 6/11 were female, and only 2/5 males had a mediastinal mass. The girls had a lower median age than boys (7 vs 9 years), none had mediastinal masses or extramedullary involvement, and their survival was greater than 27 months compared to 14 months for the boys (P less than 0.01). All patients were enrolled and treated on the (then) currently active CCSG protocols for ALL. This study emphasizes the fact that not all patients with T-cell ALL have poor prognosis, that sex could be an important factor affecting survival, and that the difference in survival could not be adequately explained by differences in the initial WBC.

Acute lymphoblastic leukemia subtypes in israel: The sheba medical center experience

During the period from 1978 to 1981, 52 patients with ALL were diagnosed and treated at the Chaim Sheba Medical Center. Using standard cell markers to subtype the blasts, 49 of the patients could be classified: 16 were found to be T-cell ALL, 10 common ALL, five null ALL, four pre-B and 14 were partially characterized as non-B, non-T. Analysis of the series revealed two distinctive features: high prevalance (30%) of T-cell ALL among both Jews and Arabs and a high proportion, two-thirds, of high risk patients due to high initial WBC counts, unfavourable age or T-cell characteristics. The minimal incidence of ALL among the Gaza Strip Arab children during the study period is 4: 100,000, which is close to the incidence in the Western world. During previous years the leukemia incidence in the Gaza Strip was very low while the most common lymphatic malignancies were Burkitt tumor and other non-Hodgkin lymphomas.

Infant leukemia in Hungary.

The treatment of childhood leukemia in Hungary is carried out in the framework of a national multicenter study. During the past ten years 633 newly diagnosed patients were treated in one of the ten centers. Of these, 39 were less than a year old at the time of diagnosis; 24 presented with ALL, 12 with AML, and three were found to have juvenile CML. Initial WBC count, which is the most important prognostic factor in childhood leukemia, was significantly higher in infants than in older children. Accordingly, the treatment results in these patients were inferior to those in children. Therapy of leukemia in infants remains a serious problem and warrants further studies to establish the best approach.

Relative Importance of Bacteremia and Viremia in the Course of Acute Fevers of Unknown Origin in Outpatient Children

During a 12-month period 80 children greater than 3 months of age seen at an emergency room with acute fevers greater than or equal to 39.7 C (103.5 F) and no localizing signs of infection were studied using blood and buffy coat cultures to isolate bacteria and viruses. Bacteremia was identified in three children (3.8%): two with Streptococcus pneumoniae and one with Neisseria meningitidis. Two children with viremia were identified: both isolates were ECHO virus, types 11 and 21, respectively. Fifty-eight of the study children (72%) were seen again in 24 to 48 hours and 27/58 (46%) were afebrile and completely well. No differences in sex, age, or initial WBC count existed among these children who returned afebrile and well and those with either localized disease or those persistently febrile.

Primary Amebic Meningoencephalitis

PRIMARY amebic meningoencephalitis is an acute, fulminating, purulent meningoencephalitis caused by free-living amebas of the genus Naegleria . It chiefly afflicts children and young adults in otherwise good health. Mortality approaches 100%. Although in this country most cases have been from the southeastern states, notably Virginia, the following case report helps to emphasize that no region is geographically immune. Report of a Case An 18-year-old man was admitted to the Tucson Medical Center, Tucson, Ariz, after a two-day history of headache, stiff neck, and fever. The patient had been in excellent health until two days before admission. He gave a history of swimming in a desert lake near Las Vegas several days before admission. The patient appeared healthy, alert, and fully oriented, although complaining of headache. His temperature was 38.2 c orally, and he had moderate nuchal rigidity. There were no other abnormal signs. The initial peripheral WBC count was 15,800/cu

Eosinophilia Associated With Psyllium Hydrophilic Colloid Ingestion

To the Editor.— Bulk-forming laxatives derived from psyllium seed are commonly used in the treatment of gastrointestinal (GI) disorders. Adverse reactions are rare. In the patient described here, eosinophilia developed from a psyllium hydrophilic colloid preparation. Report of a Case.— A 60-year-old woman was admitted to Bridgeport (Conn) Hospital because of chronic diarrhea and abdominal pain. Six weeks earlier, barium contrast studies, sigmoidoscopy, and lactose tolerance tests had given normal findings. She was believed to have an irritable colon syndrome and was treated with psyllium hydrophilic colloid, 5 mL three times a day, and a low residue diet. She denied allergies, wheezing, urticaria, rashes, dyspnea, pets, travel, hobbies, or occupational exposure. Physical findings were unremarkable. The initial WBC differential count showed a 17% eosinophilia. When no apparent cause for the eosinophilia was found, administration of the psyllium hydrophilic colloid was discontinued; within three days, the eosinophil count returned to normal

22 300 CASES OF ACUTE GRANULOCYTE LEUKEMIA IN CHILDREN

In 20 years we gathered 239 acute myeloblastic leukemias (AML), 26 promyelocytic (APLM) and 35 monoblastic (AMoL). During the same period 1300 acute lymphoid leukemias (ALL) were treated. The peak of frequency between 3 and 3 noticed in ALL is absent in granulocytic loukemias. AML. The remission rate is 54 % (33 % in adults). The higher the WBC, the worse the results. With recent protocols combining daunomycin (DNR) and aracytine the rate reaches 75 % (48 % in protocols without DNR). The survival curve in similar in adults and children with a median of 7 months. Survival is shortened by a high initial WBC or a large splenomegaly. Only 3 % of the patients are alive after 4 years. First relapse occurs mostly in bone marrow, unusually isolated in meninges (7 %). A second short remission is possible in 43 % of the cases. APML. With protocols using DNR and heparin the remission rate is 75 % with a median survival of 16 months. There is no meningeal relapses.AMoL. The remission rate is 77 % with rubidazone, 21 % without. The median survival is 6 months and the frequency of initial or secondary meningeal involvement justifies cranial X ray prevention.

Supportive granulocyte transfusion in the infected severely neutropenic patient.

The patterns and types of infection in 93 infectious episodes in 76 patients who received supportive granulocyte transfusions are presented. In this population of infected patients 86 per cent had debilitating malignancies, 88 per cent of the infectious episodes were associated with severe (less than 100/microleters) neutropenia and septicemia was documented in 56 per cent. The overall four-week survival was 71 per cent. Patients with localized infection did extremely well. Pediatric patients also responded well to the transfusion dose and schedule. Older patients (greater than 60) and patients over the age of 17 with diffuse infection did not do as well. Delay in the initiation of granulocyte transfusions after a diagnosis of serious infection was a significant factor in the group which died less than four weeks after the initial WBC transfusion. Donor reactions in nylon filtration leukapheresis and problems associated with administration of nylon filter cells are presented and discussed.

633 NEW PROGNOSTIC FACTORS IN CHILDHOOD LEUKEMIA (ALL)

Since Feb. 1975, 883 previously untreated children with ALL have been entered on a protocol designed to evaluate prognostic factors which influence induction, remission duration and survival and to identify subsets of patients with high risk of early failure. Complete marrow remission (M1) rates ranged between 91-95%. The combination of older age (>10yrs), high initial WBC (>20,000/μ1) and low serum IgG are associated with a significantly lower M1 rate. Skin test response to recall antigens, serum inhibition of blastogenesis, HLA type or PAS positivity were not prognostic of induction or remission duration. Patients in poor prognostic group (any age, initial WBC>50,000/μ1) with L1 blasts (FAB classification, Br.J.Hem 33:451,1976) had higher M1 rate than those with L2 blasts (80 vs 67%). Using the Mantel-Peto-Cox Chi square statistic for life table data, significant factors associated with poor prognosis include: WBC>20,000/μ1; age >7yrs; M3 marrow day 14; CNS disease at diagnosis; L2 lymphoblasts; decreased serum IgG and IgA; black race. Mediastinal mass is not an independent factor. None of 41 patients in low risk group (age 3-7yrs, WBC<10,000/μ1) with L1 blasts, M1 marrow on day 14, and normal Ig has sustained an adverse event (relapse or death). Identification of prognostic factors should permit more efficient and effective design of future protocols particularly for patients with good and poor prognosis.

Effect of Glucocorticoids on WBC Counts in Splenectomized Renal Transplant Recipients

Change in peripheral blood WBC and differential cell count in response to oral glucocorticoids (steroids) was examined in 36 stable renal transplant patients receiving their usual steroid dose on a daily or alternate-day steroid schedule. Three hours following steroid therapy mean WBC count had increased significantly. Mean change in WBC count was +2,400 cells/cu mm with individual values ranging from -600 to +8,000/cu mm. No differences were observed between patients receiving daily or alternate-day regimens. Changes in WBC count were due almost entirely to an increase in segmented granulocytes and a decrease in lymphocytes. there was no correlation between dose of steroid and WBC responses. However, when retested, a given patient's WBC response to a given dose of steroid was reproducible. Differences between patients, with respect to WBC response to steroids, could not be explained by differences in azathioprine dose and was not related to initial WBC count hematocrit value, age, duration of transplant, or levels of serum creatinine, BUM, or serum phosphorus. Because of the clinical importance of the WBC count in the renal transplant recipient and the potential for large and unpredictable changes in WBC count in response to steroids, WBC and differential cell count should be obtained before the morning steroid dose.

INSIGNIFICANCE OF PROGNOSTIC INDICATORS AFTER 2-YEAR SURVIVAL IN ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

52% (11/21) of our children with ALL in marrow remission for >4 years had been classified as “high risk” because of WBC > 30,000/mm3 and/or age < 2 or >7 years at diagnosis. Because of the surprisingly high percentage of “high risk” patients among our long-term survivors, we retrospectively studied 61 children with ALL followed for 2 - 12 years post-diagnosis, to determine whether there was a limited interval during which these unfavorable indicators were operative. 24 patients with WBC>30,000/mm3 had shorter first remissions, a shorter mean survival time and there were fewer survivors at 2 years (p<.005 for each). After 2 years, high initial WBC had no significant predictive value (p > .3). Survival in 14 patients with unfavorable age at diagnosis at no time differed significantly from those of favorable age. There was no correlation between WBC and frequency of CNS leukemia; but 64% (p<.1) of CNS relapses occurred in the “high risk” age group, 2/3 within 2 years of diagnosis. We conclude that: 1) the initial WBC is a valid predictor of survival for 2 years after diagnosis, but is invalid if survival exceeds 2 years; and 2) unfavorable age at diagnosis predisposes to CNS relapse in the first 2 years.

A Comparative Study of Acute Myeloblastic Leukaemia in Children and Adults

The presenting features and clinical course of 89 adults and 15 children with acute myeloblastic leukaemia (AML) presenting to a Regional Leukaemia Centre has been analysed. Remission rate was related to age, being 40% for the total adult group and 60% for all children. Young adults and children had a particularly high remission rate, whilst elderly patients faired badly. Survival diminished with increasing age and patients who entered complete remission survived for a significantly longer time (P less than 0.001) than those who did not. Adult AML differs from childhood AML, the adults having a lower remission rate, a significantly shorter survival (P less than 0.005) and almost complete absence of second remissions. Adults showed no correlation between complete remission and initial WBC or initial blast cell count, but in children there was a significant correlation (P less than 0.05) between initial total WBC and complete remission. A significant correlation between initial platelet count and complete remission could not be demonstrated in either group. Although the numbers of children are small, preadolescent children may represent a favourable sub-group, particularly those between 7 and 8 years of age.