Clinical management of aplastic anemia

Acquired aplastic anemia is a potentially fatal bone marrow failure disorder that is characterized by pancytopenia and a hypocellular bone marrow. Hematopoietic stem-cell transplantation or bone marrow transplantation (BMT) is the treatment of choice for young patients who have a matched sibling donor. Immunosuppression with either anti-thymocyte globulin and cyclosporine or high-dose cyclophosphamide is an effective therapy for patients who are not suitable BMT candidates owing to age or lack of a suitable donor. Results of BMT from unrelated and mismatched donors are improving, but presently this treatment option is best reserved for those patients who do not respond, relapse or develop secondary clonal disorders following immunosuppressive therapy. Efforts are currently underway to both improve immunosuppressive regimens and to expand the application of BMT.     

High-dose cyclophosphamide as salvage therapy for severe aplastic anemia

OBJECTIVE: The treatment options for patients with aplastic anemia who do not respond to conventional immunosuppression are limited. The aim of this study was to evaluate high-dose cyclophosphamide in patients with refractory severe aplastic anemia (SAA). MATERIALS AND METHODS: We treated 17 SAA patients with high-dose cyclophosphamide (50 mg/kg/day for 4 consecutive days) who previously did not respond to one or more courses of immunosuppressive therapy. Median age was 31 years (range 6-58); median disease duration was 14 months (range 6-58), and 8 patients met criteria for very severe aplastic anemia (absolute neutrophil count <0.2 x 10(9)/L) at the time of treatment. RESULTS: At median follow-up of 29 months, 10 patients (59%) are alive. Nine patients (53%) achieved a drug-free remission after high-dose cyclophosphamide; 4 patients achieved a complete remission and 5 patients currently meet criteria for a partial remission but continue to improve. One nonresponder to high-dose cyclophosphamide developed paroxysmal nocturnal hemoglobinuria; another nonresponder developed a myelodysplastic syndrome. In responding patients, median time to 500 neutrophils was 54 days (range 35-119), median time to the last platelet transfusion was 99 days (range 51-751), and median time to the last red cell transfusion was 125 days (range 63-796). CONCLUSION: High-dose cyclophosphamide shows promise for salvaging patients with refractory SAA.     

Bone marrow transplantation in 107 patients with severe aplastic anemia using cyclophosphamide and thoraco-abdominal irradiation for conditioning: long-term follow-up

Since 1980, 107 consecutive patients (pts) underwent bone marrow transplantation (BMT) for nonconstitutional severe aplastic anemia (SAA) at our institution. All received conditioning with Cytoxan (150 mg/kg) and thoraco-abdominal irradiation (6 Gy) from an HLA-identical sibling donor. Mean age was 19 years (5 to 46 years). Forty-nine pts had less than 0.2 x 10(9)/L PMN and 53 failed to respond to previous immunosuppressive therapy before BMT. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate (22 pts), cyclosporine (52 pts), or both (33 pts). With a median follow-up of 45 months (12 to 120 months), overall actuarial survival was 68% (confidence interval 95%:9.7). Of 16 factors tested, five were shown to adversely influence survival by multivariate analysis: grade greater than or equal to 2 acute GVHD (relative risk [RR]: 5.5), prior immunosuppressive therapy (RR: 3.5), female as donor (RR: 2.4), nonidiopathic SAA (RR: 2), and more than 0.2 x 10(9)/L PMN AA (RR: 2). Because acute GVHD was the most potent factor for survival, we analysed risk factors for acute GVHD. By multivariate analysis, 2 of 14 factors tested were independent: male as recipient (RR: 3) and previous alloimmunization of the donor (RR: 4.3). On long-term follow-up, chronic GVHD was observed in 49 pts of 89 surviving more than 100 days (55%). Multivariate analysis showed that infection before transplant (RR: 1.3) and previous history of acute GVHD (RR: 1.8) were associated with an increased risk of chronic GVHD.     

Treatment of adults with severe aplastic anemia: primary therapy with antithymocyte globulin (ATG) and rescue of ATG failures with bone marrow transplantation.

PURPOSE: To evaluate a policy of immunosuppression with antithymocyte globulin (ATG) as primary therapy for adults with severe aplastic anemia (SAA) regardless of the availability of an HLA-identical bone marrow donor. PATIENTS AND METHODS: Thirty-one consecutive adults with SAA who satisfied the age criteria for allogeneic bone marrow transplantation (BMT) (age less than 51 years) were treated with ATG 20 mg/kg/day for 10 days along with high-dose corticosteroids. Patients with an HLA-identical donor received a transplant if they did not respond to ATG or if they developed life-threatening complications during or soon after ATG administration. Eight patients with no response to ATG were also treated with oral cyclosporine 12.5 mg/kg/day. RESULTS: Eleven patients had a complete and five a partial response to ATG; two patients improved with cyclosporine treatment, resulting in an overall response rate of 58% to immunosuppression. Nine of 14 patients with donors received a BMT: seven because they did not respond to ATG and two because of serious infections. Seven grafts were obtained from related and two from unrelated donors. There was no significant difference in survival between those with and without a related HLA-identical donor (log-rank p value = 0.969). At a median follow-up of 58 months, 26 of 31 are alive with an actuarial survival of 80% at 5 years. Two patients died of infection, two died from complications of BMT, and one remains transfusion-dependent. One patient died of refractory leukemia at 30 months; one patient relapsed with hypoplasia 95 months after initial therapy with ATG. He showed a complete response to treatment with cyclosporine. No other late hematologic events have occurred. CONCLUSIONS: This treatment approach resulted in the restoration of hematopoiesis and independence from transfusion in 80% of patients with SAA entered into the study. The efficacy of allogeneic BMT in salvaging cases in which ATG failed does not appear to be compromised. Follow-up for the development of clonal hematologic disorders remains an important part of this treatment policy.     

Results of intensive therapy in childhood acute myeloid leukemia, incorporating high-dose melphalan and autologous bone marrow transplantation in first complete remission

Childhood acute myeloid leukemia (AML) has a poor prognosis with standard chemotherapy. Allogeneic bone marrow transplantation (BMT) in remission improves the outlook only for the one third of patients with sibling donors. Autologous BMT with a lower morbidity and mortality is available to all. In this study, maximum cytoreduction was achieved by intensive early chemotherapy. Final intensification, with autologous BMT was offered to all those remaining in first complete remission (CR). Patients received two induction and two consolidation courses of intensively scheduled chemotherapy. Cytoreduction was assessed on day 14 and remission was assessed after courses 2 and 4. Bone marrow was harvested after recovery from the second consolidation course or after the first maintenance course and separated on a discontinuous percoll gradient before cryopreservation. Twenty-eight of 31 consecutively enrolled patients achieved CR. Three relapsed early and, of the 25 eligible, 24 underwent autologous BMT. Twenty-three patients received high-dose melphalan and 1 received busulphan and cyclophosphamide before autologous BMT at a median of 113 days (range, 86 to 301) after initial CR. Trilineage engraftment occurred in all. Neutrophil recovery to greater than 0.5 x 10(9)/L occurred at a median of 46 days (range, 13 to 92) after autologous BMT. Platelet recovery was delayed, with a median time to achieve greater than 20 x 10(9)/L of 42 days (range, 18 to 215). With a minimum follow up of 25 months following autologous BMT only 3 children have relapsed. The 5-year event-free survival rate (EFS) from diagnosis is 68% (95% confidence interval, 46% to 90%). Five- year EFS following autologous BMT is 87% (95% confidence interval, 67% to 100%). Autologous BMT with high-dose melphalan administration after intensive chemotherapy has produced EFS equivalent to allogeneic BMT and is associated with a strikingly low relapse rate. High-dose melphalan appears to be a valuable agent for conditioning therapy in AML.     

Cyclophosphamide and other new agents for the treatment of severe aplastic anemia

Severe aplastic anemia (SAA) has a poor prognosis in the absence of treatment. Current accepted therapeutic strategies include allogeneic stem-cell transplantation and immunosuppression, both resulting in long-term survival in the majority of patients. Although human leukocyte antigen (HLA)-matched sibling stem-cell transplantation is highly effective, the 25% probability of finding a suitable sibling donor within a family renders this approach available to only a minority of patients. Transplantation using HLA-matched, unrelated donors carries a high risk of treatment failure along with considerable toxicity. While combined immunosuppression with both antithymocyte globulin (ATG) and cyclosporine A (CSA) produces hematologic improvement in most patients, relapse is common. Late evolution of aplastic anemia to other serious hematologic disorders, including paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia, and acute leukemia, is also a significant problem following treatment with ATG/CSA. Recently, results of immunosuppression in SAA with another potent immunosuppressive agent, cyclophosphamide, were reported in a small number of patients. The overall response rate was similar to that seen with ATG/CSA, but relapse and late clonal disease were not observed during a long period of follow-up. A larger randomized trial comparing sustained hematologic response rates to either conventional immunosuppression with ATG/CSA or high-dose cyclophosphamide and CSA is now underway; secondary end points include response duration, event-free survival, and overall survival. Additionally, a number of protocols designed to test the efficacy of alternative immunosuppressive or immunomodulatory agents are being developed.     

Treatment with marrow transplantation or immunosuppression of childhood acquired severe aplastic anemia: a report from the EBMT SAA Working Party

A total of 304 children under the age of 15 years with acquired severe aplastic anemia (SAA) received immunosuppressive therapy (IS) (n = 133) or a matched bone marrow transplant (BMT) (n = 171). The projected 10-year survival is 48% and 63% respectively (p = 0.002). Results following BMT have improved considerably over the years from 49% in 1970-80, to 70% in 1981-83 (p = 0.002) and to 81% between 1984-88 (p = 0.08). Other favorable prognostic factors are the use of cyclosporin A (p = 0.004), no previous therapy (p = 0.006) and early BMT (p = 0.009). In multivariate analysis only the year of treatment proved significant (p = 0.02). In contrast, results of IS are greatly dependent on the severity of pre-treatment neutropenia with survival of 56% versus 37% for neutrophils more or less than 0.2 x 10(9)/l (p = 0.003). Poor survival was associated in univariate analysis with female sex (43%), post-hepatitis SAA (37%), children not receiving androgens (38%) and patients younger than 5 years (35%), especially if associated with a low neutrophil count (11%). In multivariate analysis only the degree of neutropenia proved significant (p = 0.005). These results suggest that IS is a satisfactory alternative therapy for children with moderately SAA in the absence of an HLA-identical sibling, although BMT remains the treatment of choice. In children under 5 years with very SAA, results with IS are so poor that a search for an unrelated matched donor is justified as early as possible.     

Antirecipient helper and cytotoxic T-cell frequencies in bone marrow transplantation

We assayed helper T-lymphocyte precursor frequencies (HTLPf), interferon (IFN)-gamma-producing cell frequencies (IFN-gammaPf) and CTL precursor frequencies (CTLPf) to see if they could predict the severity of acute graft-versus-host disease (aGVHD) and disease relapse after transplantation. In all, 48 bone marrow transplantation (BMT) patients and their HLA-identical sibling (n=29) or matched unrelated donors (MUD) (n=19) were recruited. HTLPf, IFN-gammaPf and CTLPf were measured using a limiting dilution assay (LDA). Patients were followed prospectively to assess the severity of aGVHD and the status of the primary disease after BMT. High (>5 x 10(-6)) HTLPf, CTLPf and IFN-gammaPf were significantly associated with the occurrence and severity of aGVHD in patients who received transplants from HLA-identical sibling. Among patients receiving BMT from MUD, HTLPf and CTLPf, but not IFN-gammaPf, were associated with aGVHD. Five patients had disease relapse post-BMT and the risk was not significantly associated with HTLPf, CTLPf or IFN-gammaPf. Patients with high (>5 x 10(-6)) HTLPf, IFN-gammaPf or CTLPf before BMT are at higher risk of developing aGVHD after transplantation from both matched sibling donors and MUD. Whether these parameters can predict disease relapse would have to be investigated with a larger cohort of patients.     

Induction chemotherapy followed by allogeneic bone marrow transplantation or aggressive consolidation chemotherapy in childhood acute myeloblastic leukemia: A prospective study from the French Society of Pediatric Hematology and Immunology (SHIP)

In the LAME89/91 protocol, children with acute myeloid leukemia (AML) who achieved complete remission (CR) after induction chemotherapy, were treated either with allogeneic bone marrow transplantation (BMT) if they had an HLA-compatible related donor or with chemotherapy including high-dose cytarabine. The objectives of this study were to describe the overall results of this strategy and to compare the two post-remission arms. Two hundred and thirty-one children were enrolled in the protocol. Induction chemotherapy consisted of a combination of cytarabine and mitoxantrone. A CR was achieved in 204 children (88%). Fifty-one of them had an HLA-identical sibling donor and were eligible for BMT. These 51 patients, as well as two additional children who had a one antigen HLA-mismatched father, received BMT during first CR. Consequently, 53 patients were analysed in the BMT group and 151 in the chemotherapy group. With a mean follow up duration in the study of 38 ± 2 months, overall event-free survival (EFS) was 47 ± 7% at 4 years for the 231 patients entered into the protocol. The 4-year disease-free survival (DFS) was 53 ± 8% for the 204 patients who achieved complete remission after induction therapy. The 4-year probability of relapse was 28 ± 14% in the BMT group and 47 ± 9% in the chemotherapy group (p = 0.02). The risk of therapy-related death was 6.2% for BMT and 8.1% for chemotherapy. DFS was 68 ± 14% in the BMT group and 48 ± 9% in the chemotherapy group (p = 0.02). We conclude that allogeneic BMT from a matched sibling donor is the treatment of choice for reducing the relapse risk and for increasing DFS in children with AML in first CR.     

Treatment of acquired severe aplastic anemia with antilymphocyte globulin, cyclosporin A, methyprednisolone, and granulocyte colony-stimulating factor

Fifty-six adult patients with newly diagnosed acquired severe aplastic anemia (SAA) received horse antilymphocyte globulin (ALG), cyclosporin A (CyA), methylprednisolone (Mpred), granulocyte colony-stimulating factor (G-CSF) as first-line therapy. The median age was 34 (range, 17-72) and median neutrophil count 0.280 x 10(9)/L. Trilineage hematologic recovery (at a median interval of 105 days from treatment) was seen in 46 patients (37 complete, 9 partial) after one (n = 38) or two (n = 8) courses of ALG. Cytogenetic abnormalities were observed in three unresponders, clonal hematologic disease in three complete responders, and relapse of marrow aplasia in four complete responders. Median follow up for surviving patients was 1,668 days (range, 237-4,012). The actuarial survival at 5 years was 82%, falling to 77.1% at 7 years and was stationary at 7 and 8 years. Survival was not influenced by the neutrophil count (72% vs. 87%, for neutrophils less than vs. greater than 0.2 x 10(9)/L; P = 0.54). Immunosuppressive treatment of SAA with the 4-drug combination appears to be effective. The significant prognostic effect of an enduring increase of the white blood cell (WBC) count during G-CSF treatment may suggest complete and partial response to therapy. In nonresponders, the WBC count either did not change or elevated values gradually returned to nearly their initial levels while the patients were still under G-CSF treatment. In patients not responsive to treatment but living under CyA and G-CSF, the possibility of developing cytogenetic abnormalities does not seem to be low, despite the absence of findings attributable to manifest myelodysplastic syndrome.     

Bone marrow transplantation in Fanconi anemia using matched sibling donors

Eighteen patients with Fanconi anemia (FA) with evidence of bone marrow (BM) aplasia underwent allogenic BM transplants (BMT) from matched sibling donors (MSD). Median age at BMT was 7.6 years. Conditioning consisted of low-dose cyclophosphamide (CY; 5 mg/kg x 4 days) and thoracoabdominal irradiation (TAI; 400 cGy). Graft-versus-host disease (GVHD) prophylaxis included cyclosporin A and prednisone. In addition antithymocyte globulin (ATG) was administered in the pretransplant period to promote engraftment and in the posttransplant period for additional GVHD prophylaxis. Engraftment occurred rapidly (median, 12 days for an absolute neutrophil count > or = 0.5 x 10(9)/L; median, 22 days for platelet count > or = 50 x 10(9)/L). Seventeen patients have sustained engraftment and are transfusion-independent, with Lansky scores of 100% at median follow-up of 27 months. One patient developed graft failure 4 months after initial engraftment and required a second BM infusion. None of the patients developed acute GVHD; 3 patients (16%) developed chronic GVHD. BMT is a feasible option for FA patients having an MSD and should be performed at a young age and early in the course of the disease, before the development of complications. We believe the addition of ATG to the transplant regimen of low-dose CY, TAI, and cyclosporin was responsible for improvement in the survival of FA patients undergoing BMT. The regimen was well tolerated and was associated with a low incidence of complications including GVHD.     

Bone marrow transplantation for severe aplastic anemia: the Barcelona Hospital Clinic experience

BACKGROUND AND OBJECTIVE: The outcome of patients with severe aplastic anemia (SAA) has improved considerably over the last decades. Bone marrow transplantation (BMT) is the treatment of choice in young patients who have an HLA-identical sibling donor. This study analyzes the outcome and factors related to survival in patients with SAA receiving BMT in our institution. DESIGN AND METHODS: Between March 1978 and December 1996, 49 consecutive patients received an HLA-identical sibling marrow transplant for SAA. Median age was 21 years (range, 4 to 47) and 15 (31%) were women. Median interval from diagnosis to transplant was 2.6 months (range, 0.5 to 159). Between 1978 and 1982 all patients were conditioned with cyclophosphamide (CY) alone and received methotrexate (MTX) until day 102 as graft-versus-host disease (GvHD) prophylaxis. From 1983 most patients received CY and thoraco-abdominal irradiation (TAI) as the conditioning regimen and cyclosporin A (CSA) as GvHD prophylaxis. RESULTS: Survival probability at 10 years was 55 +/- 7% with a median follow-up for the surviving patients of 8.5 years. The incidences of graft failure, grade II to IV acute GvHD, and chronic GvHD were 21%, 39.5% and 31%, respectively. In multivariate analysis three factors adversely influenced survival: a) age > or = 30 years (p = 0.05); b) > or = 10 transfusion units pre-BMT (p = 0.008); and c) use of long course MTX for GvHD prophylaxis (p = 0.01). One case of squamous-cell carcinoma occurred in a TAI-treated patient 13 years post-transplantation. INTERPRETATION AND CONCLUSIONS: BMT is effective in young patients with SAA who have an HLA-identical sibling donor, particularly if minimally transfused pre-transplant. The introduction of TAI and CSA to our preparative regimen has led to a remarkably increased survival.     

Recombinant human granulocyte-macrophage colony-stimulating factor accelerates engraftment kinetics after allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia

BACKGROUND AND OBJECTIVE: The use of recombinant human granulocyte-macrophage stimulating factor (rhGM-CSF) has been shown to be well-tolerated and to reduce post-transplantation morbidity in adults undergoing HLA-identical allogeneic bone marrow transplantation (BMT). There is however, limited experience in children. DESIGN AND METHODS: We performed a prospective, comparative multicenter trial using rhGM-CSF after allogeneic BMT in children with acute lymphoblastic leukemia (ALL). The study comprised 24 patients with ALL who received rhGM-CSF and 22 patients with ALL who did not receive rhGM-CSF. There were no statistically significant differences in the demographic characteristics between the rhGM-CSF-treated and untreated groups. rhGM-CSF was given at a dose of 10 micrograms/kg/day infusion over 4 hours from day +1 until +28 or until the absolute neutrophil count (ANC) was > or = 1 x 10(9)/L. All patients received HLA-identical sibling marrow and cyclosporine alone for graft-versus-host disease (GvHD) prophylaxis. The number of cells infused was similar in both groups. A software program (Statview 4.0, Abacus Concept, Inc., Berkeley, CA, USA) was used for statistical analysis. RESULTS: The median of days to achieve ANC > or = 0.5 x 10(9)/L was shorter in the rhGM-CSF-treated patients (14 days vs 18.5 days; p < 0.0001). Patients who received rhGM-CSF had a lower incidence of grade III-IV mucositis. The duration of hospital stay was significantly shorter in patients who received rhGM-CSF (31 days vs 45 days; p < 0.005). No differences in GvHD severity, relapse or survival were observed. At the dose and schedule used in the present study, rhGM-CSF was well-tolerated and no side effects were observed. INTERPRETATIONS AND CONCLUSIONS: rhGM-CSF at a dose of 10 micrograms/kg/day in children with ALL undergoing allogeneic BMT is well tolerated, accelerates neutrophil and platelet engraftment, reduces the intensity and severity of mucositis and permits a more rapid discharge from hospital.     

Successful unrelated donor bone marrow transplantation for paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disease of hematopoiesis due to a mutation in the PIG-A gene. Affected patients may demonstrate hemolysis or venous thrombosis, and may develop MDS or aplastic anemia. Successful results may be obtained after conditioning and transplantation from syngeneic or genotypically matched sibling donors. Experience with transplantation from matched unrelated donors (MUD) is limited to eight patients, with only one survivor. We report three patients who underwent successful MUD BMT for PNH. All three patients had severe aplastic anemia (SAA) and PNH at the time of BMT. Unrelated donors were six-antigen HLA-matched (n = 2) or HLA-A mismatched (n = 1). Conditioning consisted of cytarabine, cyclophosphamide, TBI, and ATG. Grafts were T cell-depleted by anti-CD6/CD8 antibodies + complement. Further GVHD prophylaxis consisted of cyclosporine. Patients received 0.7-1.1 x 10(8) nucleated cells/kg and 1.1-2.1 x 10(6) CD34(+) cells/kg. Neutrophil engraftment occurred at 16-21 days. One patient developed grade 1 acute GVHD. Although all three patients experienced significant transplant-related complications, they ultimately resolved and all patients are alive and well 30-62 months after BMT. T cell-depleted MUD BMT is an effective treatment option for PNH-related MDS and SAA.     

Bone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia (SAA): a report of the EBMT SAA working party

This is an analysis of 509 patients with severe aplastic anaemia (SAA) treated in Europe between 1981 and 1986; 218 patients were treated by allogeneic bone marrow transplantation (BMT) from HLA identical sibling donors and 291 with immunosuppressive therapy (IS) with antilymphocyte globulin (ALG). The overall actuarial survival was 63% after BMT and 61% after IS therapy at 6 years. All patients fulfilled the criteria of SAA; however, most patients with a neutrophil count of less than 0.2 x 10(9)/l also had infections and haemorrhages. Therefore a further subclassification was defined by pretreatment peripheral blood neutrophil count: very severe aplastic anaemia (vSAA) (less than 0.2 x 10(9)/l neutrophils) and moderately severe aplastic anaemia (mSAA) (0.2-0.5 x 10(9)/l neutrophils). A Cox regression analysis showed that the only significant pre-treatment variables were a low neutrophil count (P = 0.001) and increasing age (P = 0.05). Thus it seemed reasonable to analyse survival data after combined stratification for neutrophils (vSAA versus mSAA) and age (cut off at 20 years). BMT was superior to IS in patients with vSAA under 20 years of age (64% v. 38%; P = 0.01). IS was superior to BMT in patients with mSAA aged 20 or more (82% v. 62%; P = 0.002). The two treatments gave comparable results in young patients with mSAA (BMT = 58%, IS = 62%; P = 0.1), and in older patients with vSAA (BMT = 44%, IS = 43%; P = 0.06). Overall 75/218 and 87/291 patients, given BMT or IS respectively, died. The major cause of failure in BMT patients was graft rejection (n = 22) or problems associated with graft-versus-host disease. For ALG patients the major problem was persistence of the aplasia with haemorrhage (n = 32) or infections (n = 46). This study indicates that over 60% of patients with SAA can be successfully treated with either BMT or IS. Overall survival does not differ in the two groups, though significant differences emerge after stratification for severity of the aplasia and age.     

An analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy

The CD34 antigen is expressed by committed and uncommitted hematopoietic progenitor cells and is increasingly used to assess stem cell content of peripheral blood progenitor cell (PBPC) collections. Quantitative CD34 expression in PBPC collections has been suggested to correlate with engraftment kinetics of PBPCs infused after myeloablative therapy. We analyzed the engraftment kinetics as a function of CD34 content in 692 patients treated with high-dose chemotherapy (HDC). Patients had PBPCs collected after cyclophosphamide based mobilization chemotherapy with or without recombinant human granulocyte colony-stimulating factor (rhG-CSF) until > or = 2.5 x 10(6) CD34+ cells/kg were harvested. Measurement of the CD34 content of PBPC collections was performed daily by a central reference laboratory using a single technique of CD34 analysis. Forty-five patients required a second mobilization procedure to achieve > or = 2.5 x 10(6) CD34+ cells/kg and 15 patients with less than 2.5 x 10(6) CD34+ cells/kg available for infusion received HDC. A median of 9.94 x 10(6) CD34+ cells/kg (range, 0.5 to 112.6 x 10(6) CD34+ cells/kg) contained in the PBPC collections was subsequently infused into patients after the administration of HDC. Engraftment was rapid with patients requiring a median of 9 days (range, 5 to 38 days) to achieve a neutrophil count of 0.5 x 10(9)/L and a median of 9 days (range, 4 to 53+ days) to achieve a platelet count of > or = 20 x 10(9)/L. A clear dose-response relationship was evident between the number of CD34+ cells per kilogram infused between the number of CD34+ cells per kilogram infused and neutrophil and platelet engraftment kinetics. Factors potentially influencing the engraftment kinetics of neutrophil and platelet recovery were examined using a Cox regression model. The single most powerful mediator of both platelet (P = .0001) and neutrophil (P = .0001) recovery was the CD34 content of the PBPC product. Administration of a post-PBPC infusion myeloid growth factor was also highly correlated with neutrophil recovery (P = .0001). Patients receiving high-dose cyclophosphamide, thiotepa, and carboplatin had more rapid platelet recovery than patients receiving other regimens (P = .006), and patients requiring 2 mobilization procedures versus 1 mobilization procedure to achieve > or = 2.5 x 10(6) CD34+ cells/kg experienced slower platelet recovery (P = .005). Although a minimal threshold CD34 dose could not be defined, > or = 5.0 x 10(6) CD34+ cells/kg appears to be optimal for ensuring rapid neutrophil and platelet recovery.     

Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy--The European Group for Blood and Marrow Transplantation experience

Patients with severe aplastic anemia (SAA) can be successfully treated with bone marrow transplantation (BMT) or immunosuppressive therapy (IS). The current outcome using both forms of therapy among 3,669 patients treated in Europe between 1976 and 1998 is reviewed. Significant progress has been made and the overall risk of failure is now low, with survival rates greater than 80% for both treatments. Chronic graft-versus-host disease (GvHD) remains a problem for BMT patients, and carries a high risk of lethal complications. On the other hand, IS patients are exposed to late failure due to relapse or clonal/malignant diseases. First-line BMT from identical siblings is compared with IS therapy in an intent-to-treat analysis of 1,765 patients, regardless of subsequent transplant status. The outcome of SAA patients has improved considerably over time and is influenced by patient variables such as severity of the disease and age, but also by the choice of the initial treatment.     

High-dose methylprednisolone is an alternative treatment for adults with autoimmune thrombocytopenic purpura refractory to intravenous immunoglobulins and oral corticosteroids

Eight patients with severe chronic autoimmune thrombocytopenic purpura (AITP) refractory to high-dose intravenous immunoglobulin (IVIgG) and/or oral prednisone were treated with one to three infusions of high-dose methylprednisolone (HDMP) (15 mg/kg/day). The mean platelet count before treatment was 12 ± 10 × 10⁹/L. HDMP therapy led to a safe platelet count (>50 × 10⁹/L) after 2-5 days in five patients, and a minimal platelet increase (34 × 10⁹/L) able to stop bleeding in a sixth patient. The effect of HDMP was, however, translent in four of the five responders. No side effects were observed, even in the four patients older than 70 years. HDMP thus appears to be a good alternative in emergency situations or prior to surgery for patients with AITP refractory to conventional therapy.     

Durable treatment-free remission after high-dose cyclophosphamide therapy for previously untreated severe aplastic anemia

BACKGROUND: Severe aplastic anemia is a life-threatening bone marrow failure disorder. High-dose cyclophosphamide therapy followed by allogeneic bone marrow transplantation cures the disease. However, it requires a suitable donor and carries the risk for graft-versus-host disease. A small pilot study demonstrated that high-dose cyclophosphamide therapy without bone marrow transplantation leads to durable, treatment-free complete remission. OBJECTIVE: To confirm the safety and efficacy of high-dose cyclophosphamide therapy alone in patients with severe aplastic anemia. DESIGN: Uncontrolled clinical trial. SETTING: Three tertiary care hospitals. PATIENTS: 19 patients with untreated severe aplastic anemia. INTERVENTION: Cyclophosphamide, 50 mg/kg of body weight per day for 4 consecutive days. MEASUREMENTS: Probability of response and overall survival were measured. Complete remission was defined as normal blood count for age and sex. Partial remission was defined as independence from transfusion and an absolute neutrophil count greater than 0.5 x 10(9) cells/L without growth factor support. Nonresponders were patients who remained transfusion dependent or died. Relapse was defined as no longer meeting criteria for partial or complete remission. RESULTS: The median time to an absolute neutrophil count of 0.5 x 10(9) cells/L was 49 days. The probability of survival was 84% (95% CI, 59% to 95%) at 24 months. The probability of achieving treatment-free remission was 73% (CI, 51% to 91%) at 24 months, and the probability of achieving complete remission was 65% (CI, 39% to 89%) at 50 months. No responding patients have had relapse or have developed secondary clonal disorders. CONCLUSIONS: High-dose cyclophosphamide therapy without bone marrow transplantation produces durable treatment-free remission in severe aplastic anemia. This approach deserves further study in patients with severe aplastic anemia who are not suitable candidates for allogeneic bone marrow transplantation.     

Bone marrow transplantation for severe aplastic anemia. A report of 9 cases.

9 patients with severe aplastic anemia (SAA) were treated with bone marrow transplantation (BMT). 5 were conditioned with cyclophosphamide and received and HLA-identical graft (4 patients) or a mismatched graft (1 patient): 1 rejected the graft on day 30 and died on day 34 during conditioning for a second transplant; 1 died on day 15 with acute and severe graft versus host disease (GvHD) in the absence of haemopoietic engraftment; 3 are alive and complete chimeras at 1,069, 490 and 332 days after transplantation. GvHD developed in 4 patients and was treated successfully in 3 with high dose methylprednisolone and/or antilymphocytic globulin (ALG). 4 patients were conditioned with ALG and received bone marrow from a haploidentical sibling or parent: 1 patient was refractory; 3 patients showed evidence of hematologic reconstitution, but 2 of these required a second course of ALG. 3 patients in this group are alive between 60 and 490 days; 1 patient died on day 121 of HBSAg-negative acute hepatitis.