ALBERT

Description: The effect of splenectomy on the response to random donor platelet transfusion in 15 multitransfused thrombocytopenic patients is presented. Eight patients responded poorly, with low corrected platelet count increments at 1 and 24 hours posttransfusion. These eight patients were clinically alloimmunized and had lymphocytotoxic antibody ( LCTAb ) in their sera. They responded well to closely HLA-matched transfusions. In contrast, seven splenectomized patients responded well to random donor platelets. Five of these patients had no LCTAb and no other evidence of immunization. Two patients who responded well to random donor platelets had “weak” LCTAb , and one responded to platelets presplenectomy in the presence of this antibody. Splenectomy does not improve the response to random donor platelets in alloimmunized recipients.

Description: Alloimmunization is the major complication of platelet transfusion therapy in patients with acute leukemia. To evaluate whether alloimmunization continues to be a long-term problem in patients surviving induction therapy, 114 patients with acute nonlymphocytic leukemia (ANLL) who survived more than 6 mo and who received multiple courses of chemotherapy and abundant platelet transfusions were studied. Clinical response to random donor platelets and lymphocytotoxic antibody (LCTAb) were measured pretreatment and serially throughout the study period. Fourteen patients (12%) were alloimmunized upon admission, 34 (30%) patients became alloimmunized during remission induction therapy, and 66 (58%) patients did not become alloimmunized during that period. Sixty-one of these 66 patients (92%) never became alloimmunized and responded to random donor platelets during their subsequent course despite the fact they received multiple further platelet transfusions, whereas the alloimmunized patients tended to remain alloimmunized for their entire clinical course. There was no difference in age or sex between groups, and prognostic factors predicting alloimmunization could not be detected. In greater than 90% of patients not alloimmunized at admission, the presence or absence of LCTAb after induction predicts later alloantibody production. This information can be used to plan the type of platelet transfusions (HLA-matched or random donor) needed for subsequent maintenance and induction therapy. It may also help to identify a group of patients to whom more aggressive maintenance chemotherapy may be more safely administered.

Description: In an effort to determine whether the use of leukocyte (WBC) depleted platelets could modify the development of alloimmunization, 98 adult patients with acute nonlymphocytic leukemia receiving initial induction therapy were randomized to receive standard pooled platelet concentrates (PC) or WBC-depleted PC. WBC depletion was produced by an additional centrifugation of pooled PC, with removal of 81% of WBC and an associated platelet loss of 27%. Lymphocytotoxic antibody (LCTAb) levels were monitored as a serologic marker of alloimmunization. Overall, 5 of 25 evaluable patients receiving WBC-depleted PC developed LCTAb, compared to 13/31 receiving standard PC (p = 0.071). There was no significant difference in alloimmunization rate in the subgroup of patients who had no previous exposure to histocompatibility antigens by pregnancy or prior transfusions (4/15 alloimmunized receiving WBC depleted versus 4/12 receiving standard PC). There was no difference in the number of patients in each group who required HLA-matched platelets during induction therapy. In view of the significant loss of platelets with WBC depletion, the expense and difficulty of providing WBC-poor RBC, the absence of impact on the need for HLA-matched platelets during induction, and the small potential benefit from this approach, WBC- depleted platelets should not be utilized to prevent alloimmunization in patients with leukemia.

Description: It can be impossible to identify compatible platelet donors for alloimmunized patients whose HLA type cannot be determined or who have uncommon HLA types. We have previously shown that histocompatible donors can be rapidly identified by “mass screening” of platelet concentrates (PC), which are readily available in all blood banks, using a solid-phase adherence platelet cross-matching technique. Compatible PC were given to five alloimmunized patients with multispecific HLA antibodies refractory to random donor (RD) PC and selected single-donor platelet transfusions. After transfusions which produced satisfactory responses, we identified the original whole blood donors to serve as apheresis donors. Thus, the donors selected were compatible in vitro by cross-matching, and in vivo by transfusion. Only 3% to 13% of PC cross-matched for these alloimmunized patients were potentially compatible and it was necessary to screen large numbers (65 to 205 U) of PC per patient. Eighteen of 22 PC-selected transfusions produced satisfactory increments, allowing selection of 12 donors, all of whom were willing to undergo apheresis. Ten of 12 of these single- donor transfusions were successful; the two unsuccessful transfusions were infused 2 weeks after the initial PC cross-match and were still compatible with the original serum, but incompatible with more recent serum, demonstrating a change in antibody reactivity. The HLA types of the successful single donors selected by PC cross-matching differed widely from the patients' HLA types and, therefore, these donors would not have been selected by standard approaches using HLA typing. Cross- matching large numbers of RD PC for the identification of apheresis donors is helpful in the management of the alloimmunized patient and may be of particular utility for blood centers that do not have access to HLA-typed donor pools.

Description: A number of randomized trials have recently been completed evaluating the effect of hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor) as adjuncts to the treatment of patients with acute myeloid leukemia. Most studies used the growth factors to decrease the duration of neutropenia with the hope of reducing infectious morbidity and mortality. The results of these trials are generally quite consistent. Virtually all trials showed a modest reduction in the duration of severe neutropenia with a variable effect on the incidence of severe infections, antibiotic usage, and the duration of hospitalization. There was no consistent benefit in terms of improvements in complete response rate, complete response duration, or overall survival. However, it is important that there does not appear to be an increase in the incidence of drug-resistant leukemia in trials in which the growth factor was begun after completion of the chemotherapy. Other trials administered growth factors either before or simultaneous with the chemotherapy in an attempt to enhance chemosensitivity and decrease drug resistance. None of these trials, whether conducted as part of initial induction therapy or in relapse, showed improvements in response rate or survival. Lastly, some anecdotal reports have suggested that occasional patients who receive growth factors as the only therapy for overt leukemia can achieve remission, possibly through a differentiating effect of the growth factor. However, there are very few such reports, and growth factor use in this situation is potentially dangerous and should be performed only in the context of a clinical trial. In summary, there appears to be no role at this time for priming of leukemia cells by growth factors to enhance the effect of chemotherapy, and more in vitro studies should be performed before further clinical trials of this approach. It is clear that growth factors administered after induction and possibly consolidation chemotherapy can shorten the duration of neutropenia, without a significant effect on treatment outcome. It is as yet unclear whether the use of growth factors in this fashion is cost effective.

Description: Nineteen noninfected adults receiving initial induction chemotherapy for acute nonlymphocytic leukemia (ANLL) were randomized to receive either prophylactic granulocyte transfusion or platelet transfusion alone on an alternate-day schedule. An average of 11 granulocyte transfusions (range 3--19) were administered/patient with a mean dose of 11.5 X 10(9) granulocytes/transfusion. The groups were identical with respect to age, sex, number of days on study, granulocytopenic days, percent of days receiving systemic antibiotics, febrile days, complete remission rate, and incidence of minor infection. Significant transfusion reactions were much increased in the granulocyte transfusion group (7/10 versus 1/9 in controls) and were associated with the development of lymphocytotoxic antibodies (7/10 versus 4/9 controls), refractoriness to platelet transfusion, repeated fevers, and a pulmonary infiltrate in one patient. Alloimmunization to granulocytes occurred as early as the second week in some patients complicating platelet support during induction and maintenance. No severe infections occurred in the granulocyte transfusion group while three fungal infections occurred in the controls. The high rate of alloimmunization suggests that histocompatibility considerations indicate that prophylactic granulocyte transfusion should not be routine therapy and should be studied only in investigational settings.

Description: The effect of splenectomy on the response to random donor platelet transfusion in 15 multitransfused thrombocytopenic patients is presented. Eight patients responded poorly, with low corrected platelet count increments at 1 and 24 hours posttransfusion. These eight patients were clinically alloimmunized and had lymphocytotoxic antibody ( LCTAb ) in their sera. They responded well to closely HLA-matched transfusions. In contrast, seven splenectomized patients responded well to random donor platelets. Five of these patients had no LCTAb and no other evidence of immunization. Two patients who responded well to random donor platelets had “weak” LCTAb , and one responded to platelets presplenectomy in the presence of this antibody. Splenectomy does not improve the response to random donor platelets in alloimmunized recipients.

Description: Platelet concentrates were prepared at twice the normal concentration and stored at room temperature for 7 days in either standard bags (controls) or bags to which 1 or 2 g of Amberlite resin beads charged with dibasic phosphate had been added. The resin beads served as a buffer system by providing a “slow release” form of phosphate ions as well as by binding CO2 produced during platelet metabolism. Control platelets demonstrated rapid falls in pH, ATP content, morphology score, and thrombin-induced nucleotide release after 24 hr of storage with a fall in pH to less than 6.0 by day 3. Profound ultrastructural changes and a rise in pO2, suggesting loss of platelet viability, accompanied these changes. In contrast, the resin-stored platelets remained near normal after 24 hr of storage, with preservation of discoid morphology, 95% of ATP levels, excellent ultrastructural appearance, and evidence of continued oxygen consumption after 3 days of storage. Even after 7 days of storage, ATP levels remained greater than 50% of baseline and ultrastructurally intact platelets were seen. In the 1-g resin bags the pH remained at baseline levels (6.9–7.0), while there was a rise in pH in the 2-g resin bags. These results demonstrate the beneficial effects of maintaining a higher pH during platelet storage and provide a new approach to studying the metabolic changes that occur during longer term storage.

Description: Diaziquone given as a bolus has not been effective in patients with relapsed or refractory leukemia. Because of in vitro data suggesting enhancement of diaziquone-induced cytotoxicity for human and murine leukemia cells with increased duration of drug exposure and the relatively short terminal plasma half-life of diaziquone, 49 patients (34 acute nonlymphocytic leukemia [ANLL], six chronic myelogenous leukemia in blast crisis [CML-B], five acute lymphocytic leukemia [ALL], four 2 degrees ANLL) with leukemia were given diaziquone as a continuous infusion for seven days. The maximum tolerated dose was 28 mg/m2/d for seven days. The dose-limiting toxicity was the duration of bone marrow aplasia (median, 49 days to greater than 500 PMNs in responders; range, 28 to 101 days). Nonhematologic toxicity was minimal. Responses occurred only in patients with relapsed ANLL, of whom 26 were treated at effective doses. There were six complete responses (CR) (23%) and two partial responses (PR) (8%), although five of eight responders never achieved platelet counts greater than 100,000/microL. Thrombocytopenia in these patients was felt to be a manifestation of diaziquone effect, not persistence of leukemia. The median duration of CR was 195 days (range, 88 to 860+). One patient had active CNS leukemia at the start of treatment and has had a durable (28+ month) CR in both sites of disease. Diaziquone produced prolonged aplasia in patients with secondary ANLL and CML-B (five of ten patients died aplastic), whereas patients with ALL all had regrowth of leukemia and two failed to become aplastic. The lack of significant nonhematologic toxicity and the activity in patients with relapsed ANLL render diaziquone of interest as second-line therapy or consolidation therapy in first remission for patients with ANLL.

Description: Serial evaluations of lymphocytotoxic antibody (LCTAb) and responsiveness to random donor platelet transfusion were reviewed in 234 patients who had developed LCTAb at some time during their treatment course. Seventy (30%) of these patients had significant falls in antibody levels. In 44 patients these declines occurred after further antigenic exposure was reduced either because no transfusions were administered or only histocompatible platelets were transfused. Forty patients with declines in LCTAb levels who were previously refractory to platelet transfusion were rechallenged with random donor platelets. Thirty-four of 35 clinically evaluable patients had good responses to these unmatched transfusions for 2 weeks to 36 months, and in 21 patients antibody did not return despite repeated transfusions. Thus, serial LCTAb measurements are helpful in the management of alloimmunized patients. Many patients will have decreases or a loss of LCTAb, either permanently or transiently, and can be successfully supported with more easily available unmatched random donor platelet transfusions.