After infusion of cryoprecipitate, the very prolonged bleeding time of patients with severe von Willebrand disease (vWD) is shortened but not always normalized in spite of normalization of plasma von Willebrand factor (vWF) levels. Therefore treatments that further improve primary hemostasis in severe vWD patients are needed. Since DDAVP shortens the bleeding time in a variety of bleeding disorders, we investigated in a double-blind, placebo-controlled crossover study the effects of the intravenous (IV) infusion of DDAVP (0.3 microgram/kg) on the bleeding times of 10 patients with severe vWD treated with cryoprecipitate. Their very prolonged bleeding times (greater than 30 minutes), partially corrected by the infusion of cryoprecipitate (14 +/- 2 minutes, mean +/- SEM), were further shortened by the administration of DDAVP (9 +/- 2 minutes, P less than .01) but not of saline (15 +/- 3 minutes, ns). Plasma vWF levels, raised from unmeasurable to normal values by cryoprecipitate, were not changed after DDAVP or saline. The defective deposition of platelets from eight patients onto human umbilical artery subendothelium was increased but not normalized by cryoprecipitate and was not significantly affected by DDAVP or saline. Therefore the infusion of DDAVP after cryoprecipitate may be of clinical benefit for management of bleeding episodes in severe vWD patients. Since severe vWD patients do not have releasable tissue stores of vWF, DDAVP must shorten their prolonged bleeding times independently of released vWF.

Human T-cell receptor (TCR) delta-chain diversity mainly originates from high junctional variability, since only a limited number of germline elements is available. This extraordinary diversity at the V.J junction, due to the use of two D delta elements and extensive incorporation of N nucleotides, constitutes a specific clonal marker for cell populations exhibiting rearranged TCR delta genes. To this end we amplified in vitro by polymerase chain reaction (PCR) the TCR delta junctional region of five acute lymphoblastic leukemias (ALL), isolated respective DNA fragments, and used them directly as clonospecific probes. The combination of PCR technology and hybridization to clonospecific probes permitted the detection of leukemia DNA at dilution of 1:100,000 in all five cases. Moreover, we were able to investigate one of the ALL patients 11 months after achieving continuous complete remission. Conventional Southern blot analysis failed to detect rearranged TCR genes at this stage. However, residual leukemic cells could readily be detected by PCR technique. We conclude that the strategy proposed here is a very sensitive tool to detect minimal residual disease in a significant proportion of human lymphoid neoplasias.

Since 1980, adults with acute myelocytic leukemia (AML) have been treated on two clinical studies using intensive timed sequential therapy. All patients ages 16 to 80, including those with secondary AML (SAML) and those with AML preceded by a hematologic disorder (AHD), were treated, regardless of medical complications at the time of diagnosis. The first study combined high doses of cytarabine (ara-C, AC) and daunorubicin (DRN, D) in sequence (Ac2-D-Ac) and resulted in a complete remission rate of 55%. A group of these patients selected by functional status was able to receive a second course of therapy in remission, which resulted in a disease-free survival (DFS) of greater than 40% at 7 years. Because of toxicity in that study, 114 patients were entered on a second trial initiated 4 years ago, using a less aggressive first course, with amsacrine, to achieve a stable remission (Ac2-D-Amsa). This first treatment was followed by a more intensive second course (Ac6-D-Ac). With this two-step approach, a higher complete remission (CR) rate (76% for de novo AML and 54% for SAML-AHD) was achieved, and more patients were able to receive the second course of therapy. At the current median follow-up of 26 months, the median duration of DFS and overall survival are 11 and 14 months for patients with de novo AML. Age less than or equal to 55 is the most significant prognostic factor for both prolonged DFS and overall survival, with median durations of 17 and 18 months, respectively, for these younger patients. Patients with SAML-AHD remain relatively refractory to treatment despite aggressive chemotherapy, with median durations of DFS and overall survival of 9 months and 5 months, respectively.

We report the prognostic significance of the pre-B-cell immunophenotype and other presenting features, including blast cell karyotype, in a randomized clinical trial conducted from 1981 to 1986 for children with early pre-B (n = 685) or pre-B (n = 222) acute lymphoblastic leukemia (ALL). Patients greater than or equal to 1 year and less than or equal to 21 years of age who attained complete remission were stratified by conventional risk criteria and immunophenotype and then randomized to receive continuation therapy with either of two regimens of intensive chemotherapy, designated S (standard) and SAM (standard plus intermediate-dose methotrexate, 1 g/m2 every 8 weeks). The proportions of subjects achieving complete remission in the two phenotypically defined subgroups were identical, 96%. At a median follow-up time of 42 months, the overall probability of 4-year event-free survival (+/- SE) was 63% +/- 2% (pre-B = 51% +/- 5% and early pre-B = 66% +/- 3%). Children with pre-B ALL had significantly shorter durations of continuous complete remission (P = .0004); this association included both bone marrow and CNS remissions (P = .0004 and P = .02, respectively). In a univariate Cox regression analysis of potentially important prognostic factors, the pre-B immunophenotype was significantly related to a poorer outcome, as were other recognized biologic and clinical features (eg, pseudodiploidy, older age, male sex, black race, and a higher WBC). It retained its prognostic strength in a multivariate model based on age, WBC, ploidy, and sex. The risk of failure at any point in the clinical course of a child with the pre-B immunophenotype was 1.8 times as great as that in a patient lacking this feature but otherwise having an equivalent risk status. It should be stressed that the predictive value of any of the significant characteristics identified in this study could diminish in the context of another, more effective treatment program. Nevertheless, our major conclusion, that children with pre-B ALL fare worse than those with early pre-B disease in a contemporary clinical trial has implications for stratified randomization of patients and the design of risk-specific treatment protocols.

Interleukin-2 (IL-2) therapy may improve immune reconstitution and reduce the risk of leukemic relapse in the setting of minimal residual disease by augmenting cytotoxic effector mechanisms directed at residual malignant cells. In addition, IL-2 in vitro promotes the release of cytokines including gamma-interferon (gamma-IFN) and tumor necrosis factor (TNF), which also possess antileukemic activity and can enhance granulocyte function. To determine if IL-2 infusion induces release of gamma-IFN and TNF in vivo in sufficient quantity to mediate these effects, we have measured serum levels of these cytokines and secretion by lymphocytes obtained from patients receiving this cytokine in a phase 1 trial. Serum gamma-IFN was undetectable pre-IL-2 and increased to 1.5 to 17 U/mL during IL-2 infusion (P less than .05). Culture of patient lymphocytes for 48 hours produced 1.2 U gamma-IFN/2 x 10(6) cells/mL pre-IL-2 rising to 50 U/2 x 10(6) cells/mL when the lymphocytes were obtained during therapy (P less than .05). Lymphocyte subset analysis showed that both CD3+ and CD16+ cells secreted gamma-IFN in response to IL-2. TNF secretion by lymphocytes also rose during IL-2 infusion from a mean of 5 U/mL to 14.4 U/mL (P less than .01) although no rise was seen in serum levels. The material secreted by IL-2-stimulated lymphocytes is bioactive as addition of supernatants from lymphocytes obtained during IL-2 therapy to cultures of myeloid blasts significantly inhibited clonogenic growth. IL-2-induced secretion of these cytokines mediated this inhibition as it could be partially blocked by either anti-gamma-IFN or anti-TNF antibodies. Preincubation of granulocytes with the same supernatants produced enhanced oxidative metabolism, measured by chemiluminescence in response to N-formyl-methionyl-leucyl-phenylalanine (FMLP). This effect also could be partially abrogated by anti-gamma-IFN and anti-TNF antibodies. Therefore, secondary cytokine secretion may boost granulocyte function and contribute to the antileukemic effects of IL-2 infusion in patients following bone marrow transplantation or chemotherapy.

Patients with acute nonlymphoblastic leukemia (ANL) in first remission (n = 38) or chronic myelocytic leukemia (CML) (n = 55) were given cyclophosphamide and total body irradiation, followed by marrow infusion from HLA-identical siblings. To evaluate postgrafting prophylaxis for acute graft-versus-host disease (GVHD), the patients were randomized to receive either methotrexate and cyclosporine (n = 43) or cyclosporine alone (n = 50). Methotrexate/cyclosporine significantly reduced the incidence and severity of acute GVHD, and improved early survival. This report updates the results with a 3.0 to 4.5 year follow-up. Methotrexate/cyclosporine did not interfere with sustained hematopoietic engraftment, although granulocyte recovery to 1,000/microL was delayed by five days on the average. The incidence of chronic GVHD was identical in the two groups (26% v 24%). Disease-free 3-year survival was slightly better in the methotrexate/cyclosporine group (65% v 54%), but this benefit was restricted to patients with CML (73% v 54%), while no improvement was seen in patients with ANL (41% v 41%). In contrast to patients with CML (relapse rates 8% v 9%), the early survival benefit among patients with ANL given methotrexate/cyclosporine was offset by an increase in leukemic relapses (29% v 16%).

Fifty-seven adult patients with acute promyelocytic leukemia (APL) were treated between 1974 and 1984 with daunorubicin (DNR) or 4-(9-acridinylamino)methanesulfan-m-anisidide (AMSA) in combination with arabinosylcytosine (Ara-C) and 6-thioguanine (TG); they also received prophylactic heparin. Forty-one patients (72%) achieved complete remission (CR), including 11 of 12 patients who received the AMSA-containing regimen. The incidence of early fatal hemorrhage was 14%, lower than that of earlier studies or other published reports. Elevated WBC and serum lactate dehydrogenase levels at diagnosis were associated with an increased incidence of life-threatening hemorrhage and shorter remission duration. Advanced age was an unfavorable prognostic factor for male patients. Both DNR and AMSA in combination protocols are effective treatments for APL. The incidence of CR is similar to that achieved in other types of acute nonlymphoblastic leukemia (ANLL) with the same protocols, but the median duration of remission is significantly longer in APL (24 v 9 months) and the percentage of remissions longer than 60 months is also higher in APL (35% v 5%).

The value of a postremission treatment in acute myelogenous leukemia (AML), with alternating combinations of non-cross-resistant drugs, has been prospectively assessed. Of 515 evaluable patients, 347 (67.4%) entered into complete remission (CR), following induction treatment with daunorubicin (DNR), vincristine (VCR), and cytosine arabinoside (ara-C). After one consolidation course, 248 patients were randomized for six courses of intensive maintenance: either repeated treatment with DNR-VCR-ara-C, or alternating treatment where amsacrine (AMSA) was combined with high dose ara-C on cycle 1,3, and 5 and with 5-azacytidine on cycle 2, 4, and 6. Ninety-nine patients were not randomized: 57 were introduced in a bone marrow transplantation (BMT) program, and 42 went off study, mainly for treatment toxicity or refusal. The main prognostic factors for achievement of CR were performance status, cytogenetics, and age, and for the disease-free survival (DFS): age and number of courses to CR. The rate of second remission was fairly high (64%) for patients relapsing off therapy. The DFS appeared identical (median, 53 weeks), in the two randomized arms, the alternating treatment not showing superiority to the repeated one, in spite of an increased toxicity. The median overall survival for patients achieving a CR was 90 weeks. The reason for the failure of alternating maintenance treatment to improve the DFS is probably related to an insufficient dose intensity: five patients who relapsed during maintenance arm B achieved a second CR with a more intensive combination of high-dose ara-C and AMSA. In addition, 60 patients underwent a BMT (43 allogeneic and 17 autologous). The DFS of patients treated with allogeneic BMT tended to be superior to the one obtained with the chemotherapy program. However the overall survival, as well as the event-free survival, seemed equivalent, including patients who relapsed before the planned BMT. Comparisons between allogeneic BMT, autologous BMT, and intensive consolidation during first CR deserve further prospective studies in AML.

A randomized crossover study of prophylactic immunoglobulin (IgG) therapy was performed in patients with chronic lymphocytic leukaemia (CLL) or non-Hodgkin's lymphoma (NHL). Twelve patients with hypogammaglobulinemia or a history of recurrent infections received infusions of IgG or placebo intravenously (IV) every 3 weeks for 1 year. They were then switched to the alternative preparation for another year. The number of serious bacterial infections was significantly less (P = .001; Mainland's cross-over method) in the months in which patients received IgG. Serious bacterial infections showed a trend to be associated with an IgG level less than 6.4 g/L (P = .046; Fisher's exact test).

The Southwest Oncology Group conducted a study of acute lymphoblastic leukemia (ALL) in adults over a 5-year period, testing the utility of the L-10M regimen initially described by the group from Memorial Sloan-Kettering Cancer Center. One hundred sixty-eight eligible patients were treated with this intensive combination chemotherapy regimen. One hundred fifteen (68%) achieved complete remission. With the current median follow-up time of 34.5 months, the median durations of remission, relapse-free survival, and overall survival were 22.9, 20.9, and 17.7 months, respectively. Only 35% of the patients over 50 years of age achieved a complete remission. Age was a significant prognostic factor for complete response, survival, relapse-free survival, and remission duration. In addition, a low initial WBC count was found to have a statistically significant association with longer remission duration. Responders between the ages of 20 and 49 years with WBC counts of less than 15,000 appear to have an exceptionally good prognosis.

From 1964 to 1987, the EORTC Lymphoma Group conducted four consecutive controlled clinical trials on clinical stages I and II Hodgkin's disease in which 1,579 patients were entered. From the onset the main aim of these trials was to identify the subsets of patients who could be treated safely by regional radiotherapy (RT). Therefore, several prognostic indicators were prospectively registered and progressively used in the trial protocols for the delineation of the favorable and unfavorable subgroups as soon as they were recognized of high predictive value. In the H2 trial (1972 to 1976), the histologic subtype was the only variable taken into account for the therapeutic strategy and the staging laparotomy findings were found to be of prognostic value only in patients with favorable prognostic indicators. In the H5 trial (1977 to 1982), patients were subdivided into two subgroups according to six prognostic indicators. Patients with favorable features were submitted to a staging laparotomy (lap); lap negative patients were randomized between mantle field RT and mantle field plus paraaortic RT. Disease free survival (DFS) and total survival (S) were similar in the two arms. Among patients with unfavorable features, DFS and S were significantly higher in the arm treated by combination of mechlorethamine, vincristine, procarbazine, prednisone (MOPP) chemotherapy (CT) and RT than in the arm treated by total nodal irradiation. Nevertheless, in patients below the age of 40, the overall survival rates were equivalent in the two arms. In the H6 trial, the delineation of the favorable subgroup was based on (a) absence of systemic symptoms and elevated ESR, (b) no more than one or two lymph node areas involved. The aim of the study was to assess the impact on survival of a therapeutic strategy including staging laparotomy. At a 4-year follow-up, no difference in survival was evidenced. In patients with unfavorable prognostic indicators, 3 MOPP-RT-3 MOPP were compared with 3 ABVD-RT-3 ABVD. From H1 to H5 trials, the proportion of patients having received CT during the course of the disease gradually decreased; the data suggest that a further reduction in the proportion of patients aggressively treated is conceptually possible. On the basis of the prognostic factors identified, one can delineate three subsets of patients and modulate toxic cost of the initial treatment according to the characteristics of these subsets. In the most favorable subgroup, RT alone produces high survival and CT is not justified.(ABSTRACT TRUNCATED AT 400 WORDS)

The immunophenotypes of lymphoblasts from children with newly diagnosed T-cell acute lymphoid leukemia (T-ALL, n = 101) or T-cell non-Hodgkin lymphoma (T-NHL, n = 31) were analyzed to correlate stage of thymocyte differentiation with clinical features and outcome. The 67 boys and 34 girls with T-ALL were 1 month to 18 years old (median, 8 years) with leukocyte counts ranging from 2 to 810 x 10(9)/L (median, 55 x 10(9)/L). Eighteen of these patients were black, and 70 had a mediastinal mass. Twenty-six boys and five girls with a median age of 9 years (range, 1 to 20 years) had T-NHL. Seven of these patients were black, and 24 had a mediastinal mass. The distributions of thymocyte developmental stages (early [CD7+], intermediate [CD1+ and/or CD4+ and/or CD8+], and mature [CD3+]) in cases of T-ALL and T-NHL were significantly different: 34%, 43%, and 23% v 6%, 62%, and 32% (P = .02). A comparison of the patients' clinical features according to the maturational stage of thymocytes failed to disclose significant differences in the majority of characteristics studied. However, patients with mature-stage T-NHL, with or without the addition of subjects with mature-stage T-ALL, were less likely to have a mediastinal mass (P = .02 for both comparisons). Those with intermediate-stage T-cell malignancy (T-ALL and T-NHL combined) were the subgroup most likely to have a mediastinal mass (P = .01). Response to remission induction therapy was significantly worse in the T-ALL subgroup with an early-stage phenotype: a failure rate of 21% v 0% and 6% for the two more differentiated phenotypic subgroups (P = .007). Event-free survival was not affected by thymocyte maturational stage in cases of either T-ALL or T-NHL. Despite evidence of clinical heterogeneity among the maturational stages of T-cell malignancies in children, these developmental subdivisions do not appear to be critical determinants of outcome once remission is achieved. We conclude that such phenotypes need not be included in the stratification plans for clinical trials using common induction treatment.

One hundred fifty patients with bone marrow failure were treated in three groups with antithymocyte globulin (ATG; Upjohn, Kalamazoo, MI) in a multicenter trial. Patients were assessed at 3, 6, and 12 months after initiation of treatment by three criteria: transfusion independence, clinical improvement, and blood counts. Group I consisted of 77 patients with acute severe aplastic anemia, randomized to receive either ten or 28 days of ATG. There was no significant difference between the two arms of this protocol: 47% of all patients were clinically improved and 31% were transfusion independent at 3 months. Of the severely affected patients, 27% died before 3 months; most deaths occurred early in treatment. Factors associated with survival in severely affected patients included male sex, age less than 40 years, absolute neutrophil count greater than 200/microL, and idiopathic etiology. Neutrophil counts generally increased by 8 weeks after treatment, but patients continued to show improvement to 1 year posttreatment. In Group II, 44 patients with moderate or chronic severe aplastic anemia were randomized to receive either ten days of ATG or 3 months of high-dose nandrolone decanoate. No patient initially treated with androgens recovered, but 28% of ATG-treated cases achieved transfusion independence at 3 months. Group III consisted of patients with a variety of bone marrow failure syndromes. Patients with pancytopenia and cellular bone marrow showed response rates similar to those of patients with chronic or moderate aplastic anemia.

HLA immunization is a common complication of transfusion therapy in 30% to 60% of oncohematologic patients. Evidence shows that leukocytes present in cellular blood products are the main component involved in the occurrence of HLA immunization, and several studies showed that leukocyte-poor blood products are less able to induce it. However, leukocyte-poor platelet concentrates obtained by conventional techniques, ie, centrifugation, frequently have a high level of remaining leukocytes. Cotton wool filter Imugard IG 500 can be used to obtain leukocyte-poor cellular blood products. The technique is easy to perform, even in an emergency, and can be used with either packed RBCs or platelet concentrates. Means of 97%, 92%, and 76% elimination of leukocytes are obtained for packed RBCs, pooled standard platelet concentrates, and single-donor platelet concentrates, respectively. Patients were randomized to receive either standard (control group) or filtered (leukocyte-poor group) blood products. Of 112 randomized patients, 69 were evaluable, 35 in the control group and 34 in the leukocyte-poor group. Both groups are comparable according to age, diagnosis, sex ratio, previous transfusions, and pregnancies. There is a significant difference in regard to the HLA immunization rate (31.4% in the control v 11.7% in the leukocyte-poor group, P less than .05) and frequency of refractoriness to platelet transfusions (46.6% v 11.7%, P less than .05). We conclude that this filtration technique can be an efficient means to reduce the HLA immunization rate in polytransfused oncohematologic patients.

The authors treated a total of 82 patients with Ph'-positive chronic myelogenous leukemia (CML) with recombinant interferon alpha-2b (IFN alpha-2b). Sixty-five patients in chronic phase (CP), 28 of whom were untreated and 37 pretreated, and nine patients in accelerated phase (AP), were started on IFN three times a week. Patients in CP were randomized to receive 2 or 5 X 10(6) IU/m2, while patients in AP were all given the dose of 5 X 10(6) IU/m2, in addition to concomitant chemotherapy. Patients in CP who were unresponsive to the lower dose were crossed to the higher dose. Of 63 evaluable patients in CP, 43 (68%) responded, 29 (46%) achieved complete hematologic response (CHR), and 14 (22%) achieved partial hematologic response (PHR). The response rate appeared to be significantly influenced by the IFN dose in pretreated patients. Of the nine patients in AP, two attained PHR and one CHR. More recently, eight previously untreated CP cases were submitted to daily IFN administration at doses from 2 to 5 X 10(6) IU/m2. This daily schedule was also applied to patients who had obtained, with the intermittent treatment, a PHR persisting unmodified for six months (nine patients) or an unstable CHR (five patients). Seven of the eight previously untreated patients, and five of the nine PHR patients crossed to daily IFN reached CHR. In the total series of previously untreated patients, the response rate proved to be significantly influenced by the initial risk status. Cytogenetic improvement was seen in 37 of 53 responders (70%) treated for more than 3 months, the median of Ph'-positive cells declining from 100% to 65% (range 0% to 95%). Complete suppression of Ph' chromosome was observed in one case. The cytogenetic response was persistent for over 6 months in 21 patients, but the lowest value of Ph' positivity was usually unstable. At a median follow-up of 56 weeks, 23 of 36 (64%) CHR patients remain in continued disease control with IFN. A blastic transformation (BT) occurred in seven of 21 unresponsive patients and in one of the 36 CHR patients. The authors' data confirm that IFN alpha-2b, especially at daily doses, is effective in inducing clinical and cytogenetic response in a good proportion of patients with CML in the benign phase. Longer follow-ups will define the exact influence of this agent on the natural course of the disease.

We conducted a randomized, double-blind comparison of prednisone and placebo (group I) v prednisone and azathioprine (1.5 mg/kg/day) (group II) as early treatment of extensive chronic graft-v-host disease (GVHD). Patients with platelet counts less than 100,000/microL were placed into therapy with prednisone alone (group III). All three groups received identical doses of prednisone (1 mg/kg every other day) and one double-strength trimethoprim-sulfamethoxazole (TMP-SMX) tablet twice daily. Between January 1980 and December 1983, 179 previously untreated patients were enrolled and 164 were evaluable. Patients randomized to group I (n = 63) and group II (n = 63) were well matched for prognostic factors; those placed into group III (n = 38) had more frequent acute GVHD and progressive onset of chronic GVHD. Median duration of therapy was 2 years. Complications included diabetes (5%), aseptic necrosis (5%) and infection. For groups I, II, and III, the respective incidence of infection was disseminated varicella, 11%, 24%, 34%; bacteremia, 6%, 11%, 34%; and interstitial pneumonia, 5%, 14%, 18%. Recurrent malignancy was the most frequent cause of death and did not differ significantly across the groups. Nonrelapse mortality, however, did differ: 21% in group I, 40% in group II, and 58% in group III (I v II, P = .003; I v III, P = .001). Forty patients in group I, 30 in group II, and 10 in group III survive with a minimum follow-up of 3.8 years. Karnofsky performance scores for 68 survivors are 90% to 100%, scores for seven survivors are 70% to 89% and scores for five survivors are less than 70%. Actuarial survival at 5 years after transplant is 61% in group I, 47% in group II, and 26% in group III (I v II, P = .03; I v III, P = .0001). Treatment with prednisone alone results in fewer infections and better survival than prednisone and azathioprine in standard-risk chronic GVHD. Treatment with prednisone alone is less effective in high-risk patients with thrombocytopenia, and other strategies are required.

Patients who receive desmopressin acetate (dDAVP) after cardiopulmonary bypass bleed less during operation and in the first 24 hours after operation than do patients who receive a placebo. To study the mechanism of improved hemostasis in bypass patients, we examined the relationship between von Willebrand factor (vWF) and blood loss in 70 cardiopulmonary bypass patients, one-half of whom received desmopressin intraoperatively. vWF concentration and multimeric composition were analyzed before and after bypass, after drug treatment, and 24 hours after operation. Before operation, patients with valvular disease had lower percentages of vWF high-mol-wt multimers (HMWMs) than did healthy subjects or patients with coronary artery disease, but subsequent blood loss, vWF activity, and bleeding times were not related to this finding. Irrespective of drug treatment, patients who had low preoperative vWF and who had a net loss of the protein during bypass bled more after bypass than did similar patients who had a net increase of vWF during bypass. HMWMs rose to above normal levels after bypass regardless of desmopressin infusion. Differences in the concentration of vWF between desmopressin and placebo patients after receipt of the drug, although small, were better correlated with reduced blood loss than were differences in HMWM distribution. We conclude that the beneficial effect of desmopressin on hemostasis following cardiopulmonary bypass cannot be attributed to a drug-induced change in HMWM distribution but may be related to an increase in overall vWF concentration.

Depletion of leukocytes from all blood products may decrease the incidence of alloimmunization to HLA antigens present on the white cells and thus delay the onset of refractoriness to random donor platelet support. In order to test this hypothesis, 54 patients with hematologic malignancy or marrow aplasia were entered on a prospective randomized trial using cotton-wool filtration as a method of leukocyte depletion of red cell and platelet concentrates. Forty patients were considered evaluable; 20 patients received filtered products and 20 patients in the control group received standard unfiltered products. The filter was 99% efficient in removal of leukocytes (average number of WBC/platelet product, 6 X 10(6)). Platelet loss by this technique was 8%. Alloimmunization was assessed by detection of de novo formed lymphocytotoxic and platelet specific antibodies by microcytotoxicity test, Staph A protein radioimmunoassay, and solid phase red cell adherence test. In the group receiving filtered products, three of 20 (15%) patients developed lymphocytotoxic antibodies while ten of 20 (50%) patients in the control group developed cytotoxic antibodies (P = .01 by actuarial methods). Platelet antibodies were detected in seven of ten alloimmunized patients in the control group and three of three patients in the study group. Clinical evidence of refractoriness was seen in three of 20 patients in the filtered group and ten of 20 in the control group (P = .01 by actuarial methods). The cost of filtration was a fraction of the cost of a plateletpheresis product. Filtration appears to be an effective and economical method for reducing alloimmunization and clinical refractoriness to random donor platelets in patient receiving long-term transfusion support.

High-dose methotrexate (HDMTX) added to a basic regimen of chemotherapy proved superior to cranial irradiation and sequentially administered drug pairs (RTSC) in prolonging complete remissions in children with "standard-risk" acute lymphocytic leukemia. To extend this result to more contemporary risk groups, we reclassified the patients according to methods of the Pediatric Oncology Group (POG), the Childrens Cancer Study Group (CCG), the Rome workshop, and St Jude Total Therapy Study XI. By life table analysis, 70% to 78% of patients with a favorable prognosis would remain in continuous complete remission (CCR) at 4 years if treated with HDMTX. Uniformly lower CCR rates could be expected with RTSC, especially in St Jude better-risk patients. HDMTX also would show greater efficacy than RTSC in the CCG average-risk and POG poor-risk groups, but the results appear inferior to those being achieved with intensified regimens for high-risk leukemia. Although both therapies would provide adequate CNS prophylaxis in favorable-risk groups, RTSC would offer greater protection in patients classified as being in a worse-risk group by St Jude criteria. We conclude that HDMTX-based therapy, as described in this report, would be most effective in patients with a presenting leukocyte count of less than 25 x 10(9)/L, of the white race, aged 2 to 10 years, and having leukemic cell hyperdiploidy without translocations.