Outcome of children who experience disease relapse following allogeneic hematopoietic SCT for hematologic malignancies.

Relapse after allogeneic hematopoietic SCT (HSCT) carries a poor prognosis and is a common cause of death. Outcomes of children who relapse post HSCT are not well known. In this retrospective multicenter study we included 532 patients who underwent allogeneic HSCT and examined the outcomes of 160 patients (30%) who relapsed. Treatment options after relapse included (i) palliative therapy with non-curative intent (n=43), (ii) salvage chemotherapy (without a second HSCT, n=55) or (iii) salvage chemotherapy followed by a second HSCT (n=62). Sixty two patients underwent a second HSCT. The 1-year disease-free survival (DFS) for those given palliative therapy, chemotherapy alone and who underwent a second transplant was <1%, 9% and 50% (P=<0.0001), respectively. The DFS at 1 and 2 year was 50% and 35%, respectively, among the patients who received a second transplant versus 9% and 2% in those who did not (P=<0.0001). In multivariable analysis longer time to relapse (P=0.04) and undergoing a second HSCT (P<0.001) were associated with improved outcome. Withdrawal of immunosuppressive therapy, followed by curative intent chemotherapy should be offered to all patients who relapse after an allogeneic HSCT. A second HSCT should be considered, especially in patients who respond to salvage chemotherapy.

Outcomes after HLA-matched sibling transplantation or chemotherapy in children with acute lymphoblastic leukemia in a second remission after an isolated central nervous system relapse: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research.

In children with acute lymphoblastic leukemia (ALL) with isolated central nervous system (CNS) relapse and a human leucocyte antigen (HLA)-matched sibling, the optimal treatment after attaining second remission is unknown. We compared outcomes in 149 patients enrolled on chemotherapy trials and 60 HLA-matched sibling transplants, treated in 1990-2000. All patients achieved a second complete remission. Groups were similar, except the chemotherapy recipients were younger at diagnosis, less likely to have T-cell ALL and had longer duration (> or = 18 months) first remission. To adjust for time-to-transplant bias, left-truncated Cox's regression models were constructed. Relapse rates were similar after chemotherapy and transplantation. In both treatment groups, relapse rates were higher in older children (11-17 years; RR 2.81, P=0.002) and shorter first remission (< 18 months; RR 3.89, P<0.001). Treatment-related mortality rates were higher after transplantation (RR 4.28, P=0.001). The 8-year probabilities of leukemia-free survival adjusted for age and duration of first remission were similar after chemotherapy with irradiation and transplantation (66 and 58%, respectively). In the absence of an advantage for one treatment option over another, the data support use of either intensive chemotherapy with irradiation or HLA-matched sibling transplantation with total body irradiation containing conditioning regimen for children with ALL in second remission after an isolated CNS relapse.

Long term disease-free survival in acute leukemia patients recovering with increased gammadelta T cells after partially mismatched related donor bone marrow transplantation.

Allogeneic stem cell transplantation (ASCT) has improved leukemia-free survival (LFS) in many but not all patients with acute leukemia. This is an eight-year follow-up to our previous study showing a survival advantage to patients with an increased gammadelta T cells following ASCT. gammadelta T cell levels were collected prospectively in 153 patients (acute lymphoblastic leukemia (ALL) n = 77; acute myelogenous leukemia (AML) n = 76) undergoing partially mismatched related donor ASCT. Median age was 22 years (1-59), and 62% of the patients were in relapse at transplant. Patient-donor human leukocyte antigen (HLA) disparity of three antigens was 37% in the graft-versus-host disease (GvHD) and 29% in the rejection directions. All patients received a partially T cell-depleted graft using T10B9 (n = 46) or OKT3 (n = 107). Five years LFS and overall survival (OS) of patients with increased gammadelta compared to those with normal/decreased numbers were 54.4 vs 19.1%; P < 0.0003, and 70.8 vs 19.6% P < 0.0001, respectively, with no difference in GvHD (P = 0.96). In a Cox multivariate analysis, normal/decreased gammadelta (hazard ratio (HR) 4.26, P = 0.0002) and sex mismatch (HR 1.45 P=0.049) were associated with inferior LFS. In conclusion, gammadelta T cells may facilitate a graft-versus-leukemia (GvL) effect, without causing GvHD. Further evaluations of this effect may lead to specific immunotherapy for patients with refractory leukemia.

A double-blind randomized placebo-controlled study of oral glutamine in the prevention of mucositis in children undergoing hematopoietic stem cell transplantation: a pediatric blood and marrow transplant consortium study.

Severe mucositis is a common cause of morbidity in hematopoietic stem cell transplant (HSCT) recipients. Glutamine has been shown to reduce mucositis in children receiving chemotherapy. Patients were randomized in a double-blind manner to receive glutamine or glycine at a dose of 2 g/m(2)/dose (maximum dose 4 g) twice daily until 28 days post transplant or discharge if sooner. Mucositis was graded by use of a modified Walsh scale. A total of 120 children were evaluable: 57 children received glutamine and 63 received glycine. The mean mucositis score was 3.0+/-0.3 vs 3.9+/-0.4 (P=0.07) in the glutamine and glycine groups, respectively. The glutamine group demonstrated a reduction in mean number of days of intravenous narcotics use (12.1+/-1.5 vs 19.3+/-2.8 in the glycine group, P=0.03) and total parenteral nutrition (17.3+/-1.7 vs 27.3+/-3.6 in glycine group, P=0.01). There was no statistically significant difference in toxicity between the two groups. Glutamine appears to be safe and beneficial in reducing the severity of mucositis. Strong consideration should be given to include oral glutamine supplementation as a routine part of supportive care of SCT patients.

Bone marrow transplantation from partially HLA-mismatched family donors for acute leukemia: single-center experience of 201 patients.

Between February 1993 and December 1999, 201 patients (1-59 years old, median 23) with acute leukemia (67% not in remission) underwent ex vivo T-cell-depleted (TCD) bone marrow transplants (BMT) from partially mismatched related donors (PMRD; 92% mismatched for 2-3 HLA A, B, DR antigens). Conditioning comprised total body irradiation, cyclophosphamide, cytarabine, etoposide, anti-thymocyte globulin (ATG), and methylprednisolone. Graft-versus-host disease (GVHD) prophylaxis comprised partial TCD with OKT3 (n=143) or T10B9 (n=58), steroids, ATG, and cyclosporine. The engraftment rate was 98%. The cumulative incidences of grades II-IV acute GVHD and chronic GVHD were 13 and 15%, respectively. The 5-year cumulative incidences of relapse and transplant-related mortality (TRM) were 31 and 51%, respectively. The actuarial 5-year overall survival (OS) and disease-free survival (DFS) probabilities were 19 and 18%, respectively. Patient age >15 years, active disease at transplant, donor age >25 years, and 3-antigen donor mismatch (host-versus-graft) affected the outcome adversely. The actuarial 5-year OS of four groups of patients identified based upon these risk factors was 39, 20, 13, and 0%, respectively (P<0.0001). We conclude that PMRD BMT is a potential treatment option for patients with high-risk acute leukemia who require an alternative donor transplant and fall into a group with a reasonable expected outcome.

Haploidentical vs autologous hematopoietic stem cell transplantation in patients with acute leukemia beyond first remission.

This is a retrospective comparison of partially mismatched related donor transplantation (PMRDT) and autotransplantation (ABMT) in advanced acute leukemia. Patients underwent T-cell-depleted PMRDT (n=164) or ABMT (n=131) for acute myeloid leukemia (n=130) or acute lymphoblastic leukemia (n=165). Fewer PMRDT patients were in remission (29 vs 85%; P<0.0001). The 5-year cumulative incidence of transplant-related mortality (TRM) was 52% after PMRDT and 16% after ABMT (P<0.0001). The 5-year cumulative incidence of relapse was 32% after PMRDT and 54% after ABMT (P=0.006). The actuarial unadjusted 5-year disease-free survival (DFS) was 16% after PMRDT and 30% after ABMT. In Cox's regression analysis, PMRDT (P<0.0001) and age >15 years (P=0.002) were associated with higher TRM, active disease (P=0.0021), ABMT (P=0.0074) and male sex (P=0.011) with higher relapse, and age >15 years (P=0.0007) and PMRDT (P=0.047) with lower DFS. Amongst second remission patients, TRM was higher after PMRDT (P=0.0003), relapse was higher after ABMT (P=0.034), and 5-year DFS was comparable (32% ABMT and 25% PMRDT). ABMT, if feasible, may be preferable to PMRDT in advanced acute leukemia patients since lower relapse after PMRDT is offset by higher TRM. If an autograft is not feasible because of nonavailability of autologous cells or very advanced disease, PMRDT is a potential alternative.

Allogeneic transplantation from HLA-matched sibling or partially HLA-mismatched related donors for primary refractory acute leukemia.

Allogeneic transplantation is successful in a minority of patients with primary refractory acute leukemia (PRAL). An HLA-matched sibling donor (MSD) is available only in 30-40% of the patients, whereas a partially mismatched related donor (PMRD) is available for most. We compared the outcome of 24 MSD (median age 24 years) and 19 PMRD (median age 34 years; P = 0.04) allograft recipients with PRAL. All MSD patients received non-T cell-depleted marrow whereas all PMRD patients received partially T cell-depleted marrow. All evaluable PMRD patients and 90% of the evaluable MSD patients attained CR. Six patients in each group with recurrent/persistent disease died. Ten PMRD (3-year probability 70%) and 14 MSD (3-year probability 63%) patients died of treatment-related causes. At the last follow-up, three PMRD (18-50 months; 3-year probability 14%) and four MSD (20-166 months; 3-year probability 20%) patients were alive and well. We conclude that allogeneic transplantation is a viable therapeutic option for PRAL. PMRD transplantation is a reasonable alternative in patients with no MSD, and results in similar outcome. In terms of identifying a donor and harvesting cells, a PMRD transplant is significantly quicker than an unrelated donor transplant - a point of great practical importance in the setting of failed induction chemotherapy where time is of the essence.

Colony-stimulating factors in stem cell transplantation: effect on quality of life.

Health-related quality of life (QOL) is poorest during the immediate post-transplantation period, but the impact of medical interventions during this period has not been studied. Colony-stimulating factors (CSFs), which are used to minimize short-term negative outcomes, might be expected to improve QOL; however, little is published about their impact on QOL during this period. We conducted a MEDLINE search to identify studies reporting on outcomes of stem cell transplantation (SCT) affected by the CSFs, mainly sargramostim and filgrastim. End points studied were: mucositis, incidence and type of infection, duration of hospitalization, time to myeloid engraftment, and quantity and quality of harvested cells. To impute the impact of CSFs on QOL post-SCT, we also reviewed the association between QOL and CSF outcomes in other circumstances. Data suggest that both CSFs improve QOL in the early autologous or allogeneic post-bone marrow transplantation period. Poor QOL caused by infection and increased length of hospital stay is expected to be improved by sargramostim. Time to myeloid engraftment, when negatively affecting QOL, is expected to be improved with both CSFs; however, the time to myeloid engraftment is consistently shorter with filgrastim. Current prospective trials designed to study the effects of CSFs in the immediate post-SCT period should collect QOL data.

Allogeneic bone marrow transplantation from partially mismatched related donors as therapy for primary induction failure acute myeloid leukemia.

The outcome of acute myeloid leukemia patients with primary refractoriness to conventional chemotherapy is extremely poor. Allogeneic bone marrow transplants with matched sibling or matched unrelated donors provide 10-20% disease-free survival in this setting. We analyzed our transplant experience using readily available partially mismatched related donor (PMRD) in patients with primary induction failure (PIF) AML. Between March 1994 and December 1998, 13 patients with PIF AML were transplanted from 0-3 HLA antigen mismatched donors. All 12 evaluable patients engrafted at a median of day +16. Ten (77%) patients survived at least 100 days after transplant. Acute GVHD (grade II) was observed in one of 12 patients. Chronic GVHD was seen in one of 10 patients surviving beyond day 100. The major cause of failure was relapse of disease in six occurring 3-12 months after PMRD BMT. Three patients are alive without disease 14, 36 and 45 months post BMT with Karnofsky scores of 100%. The actuarial 3-year probabilities of relapse and disease-free survival were 0.54 and 0.19, respectively. We concluded that a PMRD graft is a viable option, comparable to the use of matched related or unrelated donors, in patients with PIF AML in whom time is of the essence.

Partially mismatched related donor bone marrow transplantation as salvage for patients with AML who failed autologous stem cell transplant.

Treatment options for patients who relapse are limited and the outcome is dismal. Between August 1993 and January 1999, 17 patients, median age 26 (4-44) years, underwent T cell depleted bone marrow transplant from partially mismatched related donors (PMRD), as a salvage for AML relapsing after an autograft. The median time from auto-transplant to relapse was 7 months (1.5-24) and the interval between transplants was 10 months (3-30). All patients had active leukemia at time of transplant. Donors were siblings (n = 8), parents (n = 2), daughters (n = 4) and others (n = 3), and 82% were > or = 2 major HLA antigen mismatched with the recipient. The conditioning therapy included total body irradiation in 14 patients and was busulfan-based in three. Graft-versus-host disease (GVHD) prophylaxis consisted of partial T cell depletion along with post-transplant immunosuppression. Median day to engraftment was 16 days (12-20). Acute GVHD was seen in six patients, and chronic GVHD in four of 13 surviving beyond 100 days. Ten patients died of non-relapse causes, at 1-588 (median 77) days. Two patients relapsed at 3 and 4 months. Five patients (29%) are surviving leukemia-free 42-84 months post transplant (median 68 months). A short interval between transplants was predictive of early relapse but not mortality. Age <18 and <2 organ toxicities were marginally predictive of better survival. We conclude that BMT from PMRD is a reasonable option for patients with refractory AML post autograft.

Epstein-Barr virus-associated B cell lymphoproliferative disorder following mismatched related T cell-depleted bone marrow transplantation.

Epstein-Barr virus (EBV) is closely associated with the progressive and often fatal lymphoproliferative disorders (LPD) in post bone marrow transplantation (BMT) and immunocompromised hosts. The incidence increases significantly when alternative donors or manipulation of marrow graft are used. A total of 318 consecutive BMT from partially mismatched related family donors (PMRD) were performed between February 1993 and June 1998. Known risk factors for the development of EBV-LPD were analyzed which included HLA mismatches, T cell depletion, antithymocyte globulin (ATG), and graft-versus-host disease (GVHD). Eighteen patients (5.7%) developed EBV-LPD at a median of 137 days post BMT (range 48-617). The estimated probability of developing EBV-LPD was 0.13 (95% CI 0.07-0.19) at 5 years. The incidence of grade II to IV GVHD was 19.2%, which translated into an increased trend of EBV-LPD. No correlation with other risk factors was observed. Treatment consisted of supportive antiviral agents, tapering of immunosuppressive regimens, donor leukocyte infusions and radiation. Three patients are alive and disease-free at a median follow-up of 69 months (range 36-71). We observed a lower than expected incidence of EBV-LPD despite existing multiple high-risk factors. We believe prevention and early control of GVHD may contribute to this finding.

Evaluation of the half-life of intravenous human cytomegalovirus immune globulin in patients receiving partially mismatched related donor bone marrow transplantation.

STUDY OBJECTIVE: To evaluate the pharmacokinetics and use of intravenous human cytomegalovirus immune globulin (CytoGam) in allogeneic bone marrow transplantation (BMT). DESIGN: Prospective, nonrandomized, nonblinded, single-center study. SETTING: University teaching hospital. PATIENTS: Five consecutive patients with hematologic malignancies receiving partially mismatched related donor BMT with a uniform conditioning regimen including total body irradiation and chemotherapy. INTERVENTION: Serum immunoglobulin and cytomegalovirus (CMV) titers were measured before and 24 hours after the first CytoGam infusion on day -6 during the conditioning regimen. MEASUREMENTS AND MAIN RESULTS: These levels were measured every 5 days, and a second dose was administered when the CMV titer returned to 25-50% of the 24-hour level. The half-life of CytoGam was approximately 7 days. CONCLUSION: We believe this is the first report of CytoGam's half-life in allogeneic BMT. The information may prove vital in a future study in which the agent's potential beneficial effects can be maximized.

Partially mismatched related-donor bone marrow transplantation for pediatric patients with acute leukemia: younger donors and absence of peripheral blasts improve outcome.

PURPOSE: To extend access to bone marrow transplantation (BMT), we used partially mismatched related donors (PMRD) for pediatric patients with acute leukemia. In this report we sought to determine pretransplantation factors that might predict outcome. PATIENTS AND METHODS: Of 67 such patients, 43 had acute lymphocytic leukemia and 24 had acute myelogenous leukemia. At the time of transplantation, 41 patients were in relapse. Donors included 40 parents, 24 siblings, and three cousins. HLA disparity of two to three major antigens was detected in two thirds of the donor-recipient pairs. Conditioning therapy, including total-body irradiation and chemotherapy followed by graft-versus-host disease (GvHD) prophylaxis with partial T-cell depletion of the graft using T10B9 or OKT3, was combined with posttransplantation immunosuppression. RESULTS: Estimated probability (EP) of engraftment was 0.96 and was not affected by donor-antigen mismatch (AgMM; P =.732). EP of grades 2 to 4 acute GvHD was 0.24 and was not affected by recipient AgMM (P =.796). EP of disease-free survival was 0.26 at 3 years but improved to 0.45 when donors were younger than 30 years (P<.001). EP of relapse at 3 years was 0.41 and reduced with younger donors' age. For patients who were in relapse at the time of transplantation, absence of blasts was associated with a lower relapse rate (0.46 v. 0.84; P =. 083), similar to that of patients in remission. CONCLUSION: PMRD-BMT in pediatric leukemia resulted in high engraftment and low GvHD rates. To improve outcomes, younger donors should be sought, and clinicians should attempt to reduce peripheral blasts in patients who are in relapse.

Non-myeloablative allogeneic transplantation ('microallograft') for refractory myeloma after two preceding autografts: feasibility and efficacy in a patient with active aspergillosis.

A 59-year-old man with a 4-year history of light chain myeloma relapsing after two preceding autografts and salvage therapy with thalidomide underwent a peripheral blood stem cell (PBSC) transplant from his HLA-identical sister after conditioning with 100 mg/m2 melphalan. Graft-versus-host disease (GVHD) prophylaxis comprised cyclosporine. Despite pulmonary infiltrates and sinusitis at the time of the allograft, it was decided to proceed with the transplant because the myeloma was refractory and rapidly progressive. Sputum cultures obtained 2 days before the allograft grew Aspergillus fumigatus 2 days post transplant. A fumigatus grew repeatedly on specimens obtained post transplant. Prompt hematologic recovery was seen with full donor-type chimerism. The fungal infection subsided gradually on a combination of amphotericin B lipid complex and itraconazole. A second aliquot of donor PBSC was infused electively on day +42 to induce graft-versus-myeloma. Complete remission of the myeloma was achieved by 75 days post transplant. No acute GVHD was seen. No chronic GVHD was seen at 16 weeks when he received the third PBSC infusion. He is currently alive and well in remission 9 months post transplant. This case demonstrates the safety and potential usefulness of allogeneic PBSC transplantation with reduced-intensity conditioning in patients with markedly compromised performance status.

Donor leukocyte infusion for treatment of graft rejection post partially mismatched related donor bone marrow transplant.

Graft rejection following bone marrow transplantation is more common in patients who receive their grafts from alternative donors and whose marrow is T cell depleted. Rejection in these patients is mediated by persistent host cells that interfere with successful establishment of donor-derived hematopoietic recovery. We describe a patient with chronic myelogenous leukemia in accelerated phase who rejected a T cell-depleted bone marrow graft, 2 months following partially mismatched related donor bone marrow transplant. Unmanipulated peripheral blood donor leukocyte infusion, without additional chemotherapy or immunosuppressive therapy resulted in complete hematopoietic recovery. Cytogenetics and RFLP demonstrated hematopoietic donor chimerism. The patient did not develop graft-versus-host disease.

Phenotypic and functional reconstitution of peripheral blood lymphocytes following T cell-depleted bone marrow transplantation from partially mismatched related donors.

Myeloablative chemotherapy followed by transplantation of a T cell-depleted bone marrow graft from a partially mismatched related donor provides a potentially curative option for patients with leukemia and other disorders of hematopoiesis, although the patient is faced with a period of sustained immunodeficiency as well as pharmacologic immunosuppression as a result of prophylaxis against graft-versus-host disease. Thirty patients who received one to three antigen T cell-depleted mismatched grafts were evaluated for immune reconstitution. The percentage and numbers of cells expressing lymphocyte subset antigens were determined by flow cytometry at 14, 28, 60, 100, 180, 270 and 365 days post-BMT and at 6 month intervals thereafter. Lymphocyte reconstitution was characterized by the early appearance of natural killer cells and a low percentage of both T and B cells. During the first year after BMT, the number of NK cells remained constant while T and B cells gradually returned to normal numbers and proportions. Response to the lymphocyte mitogen phytohemagglutinin returned to normal over the course of 2 years, while the response to concanavalin A was slightly depressed and the response to pokeweed mitogen became supranormal at about 1.5 years and continued to increase. These data suggest the need for long-term immunophenotypic monitoring as well as prolonged infection surveillance and prophylaxis.

Late onset Epstein-Barr virus-associated lymphoproliferative disease after allogeneic bone marrow transplant presenting as breast masses.

We report a patient who developed breast masses 17 months after a T cell-depleted partially mismatched related donor (PMRD) bone marrow transplant (BMT) for chronic myeloid leukemia. The patient had severe chronic graft-versus-host disease (GVHD) and the masses were due to Epstein-Barr virus (EBV) lymphoproliferative disease (LPD). The patient expired from fungal pneumonia after chemotherapy for the EBV-LPD.

Use of partially mismatched related donors extends access to allogeneic marrow transplant.

Most patients requiring allogeneic bone marrow transplant (allo-BMT) do not have an HLA-matched sibling donor. A phenotypically matched unrelated donor graft has been made available for approximately 50% of Caucasians and less than 10% of ethnic and racial minorities in need. However, almost all patients have a readily available partially mismatched related donor (PMRD). We summarize our experience with 72 patients who ranged from 1 to 50 years of age (median, 16 years) and who were recipients of a PMRD allo-BMT from haploidentical family members following conditioning therapy using total body irradiation (TBI) and multiagent, high-dose chemotherapy. T-cell depletion and post-BMT immunosuppression were combined for graft-versus-host disease (GVHD) prophylaxis. The probability of engraftment was 0.88 at 32 days. Six of 10 patients who failed to engraft achieved engraftment after secondary transplant. Grade II to IV acute GVHD was seen in 9 of 58 (16%) evaluable patients; extensive chronic GVHD was seen in 4 of 48 (8%) evaluable patients. There was a statistically significant difference in 2-year survival probability between low-risk and high-risk patients (0.55 v 0.27, P = .048). Prognostic factors that affected outcomes in multivariate analysis were (1) a lower TBI dose and 3-antigen rejection mismatch decreased stable engraftment (P = .005 and P = .002, respectively); (2) a higher T-cell dose increased acute GVHD (P = .058); (3) a higher TBI dose increased chronic GVHD (P = .016); and (4) a high-risk disease category increased treatment failure from relapse or death (P = .037). A PMRD transplant can be performed with acceptable rates of graft failure and GVHD. Using sequential immunomodulation, the disease status at the time of transplant is the only prognostic factor significantly associated with long-term successful outcome after PMRD allo-BMT. When allogeneic rather than autologous BMT is indicated, progression in disease status before transplant can be avoided using a PMRD with equal inclusion of all ethnic or racial groups.

De novo chronic graft-versus-host disease presenting as hemolytic anemia following partially mismatched related donor bone marrow transplant .

Chronic graft-versus-host disease (cGVHD) is a disease of immune dysregulation that resembles an autoimmune disease. It usually involves the skin, mucosal and serosal surfaces and, less commonly, the hematopoietic system. We report hemolytic anemia (HA) as the primary manifestation of de novo cGVHD in recipients of partially mismatched related donor transplants. Five of 40 eligible patients developed HA at a median of 168 days post-transplant. Recipients were mismatched for one to three major HLA antigens. Conditioning therapy consisted of total body irradiation, etoposide, Ara-C, cycle-phosphamide and steroids. GVHD prophylaxis included partial T cell depletion, using anti alpha/beta CD3 antibody (T10B9) and complement, in addition to post-transplant immunosuppression. At presentation, all patients were receiving cyclosporine with or without low-dose steroids. Along with a mean Hb of 7.1 g%, patients had an increased reticulocyte count, a mild raised lactic dehydrogenase and a positive Coombs' test (in 2/5 patients). Four patients had also demonstrated a decrease in platelet count. Treatment was initiated with high-dose steroids and intravenous gamma globulin and response was observed within 1 week. Awareness of this presentation of cGVHD and early therapeutic intervention can result in successful reversal of presumed immune-mediated red cell and platelet destruction.