Evaluation of erythropoiesis after bone marrow transplantation: quantitative reticulocyte counting

Erythroid regeneration is an important and separate element in the engraftment process in allogeneic and autologous bone marrow transplantation (alloBMT, autoBMT). Qualitative visual reticulocyte counting has proved inadequate in the evaluation of erythropoiesis after BMT but automated flow cytometry now allows the reliable quantitation of reticulocytes even to very low levels. Reticulocyte counts and highly fluorescent reticulocyte (HFR) counts (very early reticulocytes) were estimated daily in recipients of 22 autoBMT and 14 alloBMT using a Sysmex R-1000 automated reticulocyte counter. Marrow ablation caused an immediate and rapid fall in both the reticulocyte count and the HFR. Measurable numbers of reticulocytes persisted throughout the hypoplastic period, but HFR fell to zero in the majority of both the autoBMT and alloBMT. HFR rose significantly after a median time of 14 d post-autoBMT, and 12 d post-alloBMT. Attainment of 15 x 10(9)/l reticulocytes and 0.5 x 10(9)/l HFR at day 21 post-transplant was associated with ultimate engraftment in 100% cases. Inadequate engraftment was seen in the majority of patients whose responses fell below these levels. Graft-versus-host disease was associated with a transient slight reduction in reticulocyte count. Neither episodes of infection nor blood transfusions had any significant impact on trends of reticulocytes or HFR. Automated flow cytometric reticulocyte counting has been shown to provide an accessible measure of erythroid activity which may be of predictive value in the management of patients following bone marrow transplantation.     

Kinetics of hemopoietic recovery after peripheral blood stem cell transplantation: impact of stem cell purification and G-CSF

We investigated the role of stem cell purification and G-CSF (early vs. delayed vs. no G-CSF) administration on hemopoietic recovery and supportive care requirements after stem cell transplantation. Thirty-two patients submitted to autologous CD34(+) peripheral blood stem cell transplantation (PBSCT) were studied, and data were compared to patients undergoing unfractionated peripheral blood stem cell transplantation (uPBSCT) matched for age, disease, and conditioning regimen. Except for PMN, hemopoietic recovery was significantly slower and supportive care requirements were significantly higher after CD34(+) PBSCT. Median time to PMN >0.5 x 10(9)/l was 13 days (range 9-27) and 13 d (range 9-23); reticulocytes (Ret) >1% was 14.5 d (range 12-34) and 12 d (range 10-27); high-fluorescence reticulocytes (HFR) >5% was 12 d (range 9-26) and 9 d (range 7-11); platelets >50 x 10(9)/l and >100 x 10(9)/l was 20 d (range 10-240), 12 d (range 9-60) and 33 d (range 15-720), 15 d (range 11-210). When the analysis was performed on subgroups of patients (early/delayed/no G-CSF), early G-CSF significantly promoted PMN recovery (>0.5 x 10(9)/l and >1.0 x 10(9)/l) compared to no G-CSF, without affecting RBCs or platelet recovery. Delayed G-CSF did not improve PMN recovery compared to patients not receiving G-CSF, did not result in a significant reduction of drug requirements, and had a negative impact on erythroid and platelet recovery. In conclusion, these preliminary data suggest that G-CSF is useful if given early after CD34(+) PBSCT. CD34(+) PBSCT may overall require a significant increase of resource utilization that should be outweighed by proven clinical benefit.     

Effectiveness of low dose cyclosporine in acquired aplastic anaemia with severe neutropenia.

Six patients with acquired aplastic anaemia were treated with cyclosporine (5 mg/kg/day) either alone or in combination with corticosteroids. A favourable response was observed in 4, including 2 patients presenting with an absolute granulocyte count of less than 0.2 x 10(9)/l. The 6th patient showed no effect after 6 wk of therapy and was thereafter successfully treated with anti-thymocyte globulin (ATG). Side effects of cyclosporine therapy were minimal (maximum follow-up 20 months). Temporary discontinuation of the drug in 1 patient resulted in a relapse which responded to reinstitution of therapy. Our results indicate that cyclosporine may be an effective, well-tolerated agent in acquired aplastic anaemia even in previously untreated patients with severe neutropenia.     

Successful treatment with immunosuppressive therapy for aplastic anemia developed after resection of thymoma

We report here a very severe case of thymoma-related aplastic anemia that developed after thymectomy. The patient was a 50-year-old man diagnosed with myasthenia gravis. Chest CT showed thymoma measuring 7.5 cm in diameter, and extended thymectomy was performed. Irradiation to the anterior mediastinum was added postoperatively. Thirteen months after surgery, hemogram showed severe neutropenia: leukocyte count 0.32×10(9)/l with 11% neutrophils; Hb 10.7 g/dl; and platelet count 100×10(9)/l. Although cyclosporine (CSP, 5 mg/kg/day) was administered, dose reduction was necessary because of renal damage. Cytopenia deteriorated to a leukocyte count of 0.71×10(9)/l with 21% neutrophils; Hb 5.9 g/dl; and platelet count 24×10(9)/l. However, addition of antithymocyte globulin (ATG, 15 mg/kg) led to hematopoietic recovery of all three lineages within one month. He is clinically stable with no transfusion requirement after 22 months with CSP maintenance therapy. Although thymoma-related aplastic anemia has been reported to have an extremely poor prognosis, high efficacy of CSP has been reported recently. In our case, ATG in combination with CSP was efficient. Adequate immunosuppressive therapy seems to be important for the clinical management of these patients.     

Immunosuppressive therapy for aplastic anemia in children: a more severe disease predicts better survival

Severe acquired aplastic anaemia (SAA) is a life-threatening disease characterized by pancytopenia and hypoplastic bone marrow. Autologous T lymphocytes are thought to cause bone marrow failure by immune-mediated excessive apoptosis of stem and progenitor cells. The disease is subclassified into a severe (neutrophil count, > 0.2 x 10(9)/L [> 200/microL]) and a very severe (< 0.2 x 10(9)/L [< 200/microL]) (vSAA) form. We report the results of a prospective multicenter trial with a combined immunosuppressive regimen of cyclosporin A (CSA), anti-thymocyte globulin (ATG) and, in cases with neutrophil counts fewer than 0.5 x 10(9)/L (< 500/microL), granulocyte colony-stimulating factor (G-CSF) for treatment of SAA in children. Children with vSAA showed a higher rate of complete response than did children with SAA (68% versus 45%; P = .009), as well as better survival (93% versus 81%; P < .001). Thus, in children with SAA a more severe disease stage at diagnosis indicates a favorable outcome with immunosuppressive therapy.     

Fludarabine, cyclophosphamide and horse antithymocyte globulin conditioning regimen for allogeneic peripheral blood stem cell transplantation performed in non-HEPA filter rooms for multiply transfused patients with severe aplastic anemia

Multiply transfused patients of severe aplastic anemia are at increased risk of graft rejection. Five such patients underwent peripheral blood stem cell transplantation from HLA-identical siblings with a fludarabine-based protocol. The conditioning consisted of fludarabine 30 mg/m(2)/day x 6 days, cyclophosphamide 60 mg/kg/day x 2 days and horse antithymocyte globulin (ATG) x 4 days. Two different ATG preparations were used: ATGAM (dose 30 mg/kg/day x 4 days) or Thymogam (dose 40 mg/kg/day x 4 days). Engraftment: median time to absolute neutrophil count (ANC) >0.5 x 10(9)/l was 11 days (range: 8-17) and median time to platelet count >20 x 10(9)/l was 11 days (range: 9-17). At a median follow-up of 171 days (range: 47-389), there has been no graft rejection and all patients are in complete remission. Acute GVHD (grade 1) occurred in one patient only. Chronic GVHD developed in two patients (extensive in one and limited in another). The transplants were performed in non-HEPA filter rooms. In only one patient, systemic antifungal therapy (voriconazole) was used. The use of Thymogam brand of ATG for conditioning is being reported for the first time. Our experience suggests that this fludarabine-based protocol allows rapid sustained engraftment in high-risk patients without significant immediate toxicity.     

Optimal timing of G-CSF administration after CD34+ immunoselected peripheral blood progenitor cell transplantation.

G-CSF accelerates neutrophil recovery after autologous peripheral blood progenitor cell transplantation (aPBPCT), although the optimal timing for its administration is currently unknown. In order to establish the role and the optimal timing of administration of G-CSF after immunoselected CD34+ aPBPCT, we analyzed the data from 21 consecutive patients affected by haematological malignancies. Patients were randomized into three groups according to G-CSF administration after transplantation: day +1 (group B); day +7 (group C) or no G-CSF (group A). Serum G-CSF level was evaluated until engraftment. The CD34+ cell dose reinfused was similar (P = 0.48). G-CSF significantly reduced time to recovery of PMN >0.5 x 10(9)/l (11 vs 14 vs 20.5 days) (P= 0.00046); >1.0 x 10(9)/l (12 vs 15 vs 22) (P = 0.001). No difference was observed in the number of days with PMN <0.1 x 10(9)/l (5.5 vs 7 vs 8 days). Platelet count >50 x 10(9)/l and >100 x 10(9)/l, reticulocytes >1%, length of hospitalization, non-prophylactic antibiotic therapy, fever, incidence of sepsis and transfusion support did not differ. Early or delayed G-CSF after immunoselected CD34+ aPBPCT significantly accelerated PMN recovery but did not reduce the amount of supportive treatment or the duration of hospitalization. Delaying the initiation of G-CSF did not reduce the length of treatment (11.5 vs 12 days). Early or delayed G-CSF administration resulted in G-CSF peak serum levels 7 (early)-12 (delayed)-fold greater than an endogenous response to neutropenia.     

Cyclosporine therapy of aplastic anaemia, congenital and acquired red cell aplasia

We treated 22 patients with severe aplastic anaemia refractory to antithymocyte globulin (ATG) with cyclosporine, alone or in combination with prednisone. Eight patients showed significant clinical improvement, all but one to transfusion-independence. Although cyclosporine alone was effective, the addition of prednisone resulted in prompter and fuller haematologic improvement. No patient with an absolute granulocyte count less than 0.2 x 10(9)/l responded to treatment. Haematologic remissions were sustained beyond the treatment period. Of nine patients with Diamond-Blackfan syndrome, one showed a complete response to two separate courses of cyclosporine and relapse with withdrawal of therapy, and a second achieved significant reduction in corticosteroid dose without relapse; however, seven cases failed to respond. Two of three adults with acquired pure red cell aplasia recovered. A combination of cyclosporine and corticosteroids may be effective therapy in patients with aplastic anaemia who have failed ATG treatment. Occasional cases of congenital and acquired pure red cell aplasia may also respond to cyclosporine.     

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.     

The role of antilymphocyte globulin in the treatment of chronic acquired bone marrow failure

Antilymphocyte globulin is an immunoglobulin preparation prepared from heterologous serum after the animal (horse or rabbit) has been immunised with human lymphocytes, obtained from the thymus (antithymocyte globulin, ATG) or thoracic duct (antilymphocyte globulin, ALG). The rationale for the use of ALG in the treatment of chronic acquired marrow failure is based on its immunosuppressive activity and the fact that a proportion of cases of bone marrow failure, whether affecting single or multiple haemopoietic cell lines are due to immune-mediated suppression of haemopoiesis. In addition, in vitro studies have shown that ALG also has an immunostimulatory effect on lymphokine and haemopoietic growth factor production, and may therefore directly stimulate haemopoietic progenitor cells. ALG has been used for the treatment of aplastic anaemia and acquired chronic marrow failure affecting single cell lines namely pure red cell aplasia (PRCA), amegakaryocytic thrombocytopenia and chronic neutropenia due to immune inhibition of granulopoiesis ('acquired white cell aplasia'). ALG is used for treatment of non-severe aplastic anaemia (NSAA) and in those cases of severe aplastic anaemia (SAA) where allogeneic transplantation is not possible or is not indicated. Treatment with ALG results in 75% long term survival for NSAA and 40-50% for SAA although there is a very severe subgroup of SAA defined by peripheral blood neutrophils of less than 0.2 x 10(9)/l who rarely benefit from ALG therapy. For those patients who do not respond a second course of ALG can be given later using ALG from a different animal source.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anthracyclines added to the conditioning regimen for allogeneic bone marrow transplantation are associated with a slower haematopoietic recovery

Factors which may influence haematopoietic recovery after allogeneic bone marrow transplantation were analysed. Forty-six evaluable patients transplanted with lymphocyte-depleted marrow for acute lymphoblastic leukaemia, acute non-lymphoblastic leukaemia, chronic myeloid leukaemia, myelodysplastic syndrome and severe aplastic anaemia were studied. The median time for platelet recovery to greater than or equal to 20 and to greater than or equal to 50 x 10(9)/l was 21 (9-72) and 26 (11-86) days respectively. The neutrophil recovery to greater than or equal to 0.5 x 10(9)/l and the leucocyte recovery to greater than or equal to 1.0 x 10(9)/l was 19 (8-47) and 18 (6-47) days respectively. No relation was found between the number of infused granulocyte-macrophage colony-forming cells, erythroid burst-forming cells, diagnosis, graft-versus-host disease, antibiotic administration and recovery. Addition of a continuous 6-day infusion of anthracyclines to the conditioning regimen delayed the median recovery of platelets, neutrophils and leucocytes by 7-9 days. Fever during aplasia also inhibited haematopoietic recovery. It is speculated that leakage of intracellular anthracyclines after bone marrow infusion or fever secondary to anthracyclines-induced oromucositis is responsible for the delayed bone marrow recovery.     

Peripheral blood vs bone marrow as a source for allogeneic hematopoietic stem cell transplantation.

In this randomized prospective study, we included 30 patients with different hematological diseases (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome or severe aplastic anemia) to compare peripheral blood stem cells (PBSC) (15 patients; mean age 23) and bone marrow (BM) (15 patients; mean age 21.8) as a source for allogeneic transplantation regarding the tempo of hematopoietic recovery and the incidence of acute graft-versus-host disease (GVHD). In the BM group, the median nucleated cell count harvested was 1.3 x 10(10), while in the PBSC group, the aphereses contained a median of 4.4 x 10(6) CD34+/kg recipient weight. PBSC transplantation (PBSCT) was associated with faster hematopoietic reconstitution measured as absolute neutrophil count (ANC) >0.5 x 10(9)/l (log-rank P value <0.0018) and platelet count >25 x 10(9)/l (log-rank P value <0.0098). Seven patients (46.7%) in the BM group vs only one patient (6.7%) in the PBSC group developed acute GVHD (P = 0.013). Therefore, we conclude that PBSCT is associated with faster hematopoietic recovery and the incidence of acute GVHD does not exceed that seen with BMT.     

Antilymphocyte globulin, cyclosporin, and granulocyte colony- stimulating factor in patients with acquired severe aplastic anemia (SAA): a pilot study of the EBMT SAA Working Party

Patients with severe aplastic anemia (SAA) and a neutrophil (PMN) count of less than 0.5 x 10(9)/L are exposed to a high risk of early mortality when treated with antilymphocyte globulin (ALG) and steroids, with the major problem being infectious complications. The addition of human recombinant granulocyte colony-stimulating factor (rhG-CSF) to ALG may reduce early mortality by improving neutrophil counts in the short term. To test the feasibility of this approach, the SAA Working Party of the European Group for Blood and Marrow Transplantation (EBMT) designed a pilot study that included rhG-CSF (5 micrograms/kg/d, days 1 through 90), horse ALG (HALG; 15 mg/kg/d, days 1 through 5), methylprednisolone (2 mg/kg/d, days 1 through 5, then tapering the dose), and cyclosporin A (CyA; 5 mg/kg/d orally, days 1 through 180). Patients with newly diagnosed acquired SAA (untreated) and with neutrophil counts of < or = 0.5 x 10(9)/L were eligible. Forty consecutive patients entered this study and are evaluable with a minimum follow up of 120 days: the median age was 16 years (range, 2 to 72 years), the interval from diagnosis to treatment was 24 days, and the median PMN count was 0.19 x 10(9)/L. Twenty-one patients had hemorrhages, and 19 were infected at the time of treatment. Overall, treatment was well tolerated: the median maximum PMN count during rhG- CSF administration was 12 x 10(9)/L (range, 0.4 x 10(9)/L to 44 x 10(9)/L). There were three early deaths (8%) due to infection. Four patients (10%) showed no recovery, whereas 33 patients (82%) had trilineage hematologic reconstitution and became transfusion- independent at a median interval of 115 days from treatment. Median follow up for surviving patients is 428 days (range, 122 to 1,005). Actuarial survival is 92%: 86% and 100% for patients with PMN counts less than 0.2 x 10(9)/L or between 0.2 x 10(9)/L and 0.5 x 10(9)/L, respectively. This study suggests that the addition of rhG-CSF to ALG and CyA is well tolerated, is associated with a low risk of mortality, and offers a good chance of hematologic response. This protocol would appear to be an interesting alternative treatment for SAA patients with a low PMN count who lack an HLA-identical sibling.     

Prognosis in aplastic anaemia: a review of 138 cases

The outcome of 138 patients with aplastic anaemia was studied to ascertain whether prognostic factors at the onset of the disease are predictive. Applying four classic prognostic criteria, two groups of patients were identified: (1) those with an absolute granulocyte count of less than 0.5 × 10⁹/l, platelet count less than 20 × 10⁹/l, reticulocyte count less than 15 × 10⁹/l, and non-myeloid marrow cellularity greater than 75% who had 100% mortality in the first three months from the onset of the disease, (ii) patients who fulfilled three or fewer of these criteria who had a 20% three month mortality. The survival of these groups differed significantly (P = less than 0.001). The variable that most closely correlated with prognosis was the number of non-haematopoietic cells in the bone marrow aspirate. When Lynch's prognostic formula for patients with aplastic anaemia was applied to the same group of patients, the correlation with prognosis was less close and the calculations were tedious. The identification of a group of patients with severe aplastic anaemia is important because these patients do not benefit from conventional forms of therapy and alternative approaches such as transplantation and immunosuppression are justified.     

Long-term follow-up of allogeneic stem cell transplantation in patients with severe aplastic anemia after conditioning with cyclophosphamide plus antithymocyte globulin

We investigated the efficacy of an antithymocyte globulin/cyclophosphamide preparative regimen prior to allogeneic stem cell transplantation from HLA-identical siblings in patients with severe aplastic anemia. Since 1990, 21 patients, 6 males and 15 females, with a median age of 25 years (range: 7-43) have been enrolled in the protocol consisting of 200 mg/kg cyclophosphamide and 90-120 mg/kg antithymocyte globulin (ATG, rabbit, Fresenius, Bad Homburg, Germany). For further graft-versus-host disease (GVHD) prophylaxis all patients received cyclosporin A and a short course of methotrexate (MTX). Only one patient had a primary graft failure (5%). All other patients engrafted with a leukocyte count >1.0 x 10(9)/l and a platelet count >20 x 10(9)/l after a median of 19 (range: 11-28) and 26 days (range: 13-67), respectively. No late graft failure or relapse was observed. Two patients experienced mild acute GVHD grade I (10%), and one patient developed grade II GVHD (5%). No severe grade III/IV GVHD was observed; 17% of the patients developed limited chronic GVHD. The treatment-related mortality was 14% and mainly due to fungal infection. After a median follow-up of 70 months (range: 2-139), the estimated overall and event-free survival at 10 years for all patients is 86% (95% confidence interval: 70-100%). We conclude that ATG plus cyclophosphamide is an effective conditioning regimen in patients with aplastic anemia undergoing stem cell transplantation with a low treatment-related mortality, resulting in an excellent outcome.     

Autologous bone marrow transplantation in patients with non-Hodgkin's lymphoma: comparison of different parameters in predicting the kinetics of haematological recovery

We analysed the kinetics of haematological recovery after autologous bone marrow transplantation (ABMT) in 31 patients with non-Hodgkin's lymphoma, of whom 14 had received chemotherapy and 17 had received no chemotherapy before marrow harvesting. The time for recovery of polymorph (PMN) and platelet numbers was assessed in relation to patient's sex, age, the numbers of mononuclear cells (MNC) and of granulocyte-macrophage colony-forming cells (CFU-GM) reinfused, the therapy before harvesting and the conditioning regimens. The results showed that the most important factor influencing the speed of haematological recovery was therapy before marrow collection; recovery was faster in patients not treated before harvesting than in those treated. The mean day for PMN recovery to 0.5 x 10(9)/l was 14.6 vs 21.8 (p less than 0.001); the mean day for platelet recovery to 50 x 10(9)/l was 16.5 vs 44.4 (p less than 0.00002). The other parameters assessed did not correlate with the kinetics of haemopoietic recovery. We conclude that NHL patients who undergo ABMT without chemotherapy prior to marrow harvest have rapid haematological recovery, which suggests that better timing of the harvest could be of value in the management of NHL patients for whom 'reinforcement' with ABMT is scheduled.     

Autologous bone marrow transplantation in non-Hodgkin's lymphoma patients: effect of a brief course of G-CSF on harvest and recovery.

This study compares harvest and hematological recovery data of 100 lymphoma patients who underwent BM harvest either after a short course of G-CSF (16 microg/kg for 3 days) (n = 57) or in steady-state conditions (n = 43). G-CSF allowed the attainment of a significantly higher median number of total nucleated cells x 10(8)/kg (4.4, range 1.4-17, vs 2.1, range 0.6-4.2; P < 0.0001), mononuclear cells x 10(8)/kg (0.55, range 0.20-1.4, vs 0.41, range 0.15-0.76, P < 0.0001) and CFU-GM/ml (310, range 10-5500, vs 80, range 10-3800, P = 0.008), with lower volumes of blood collected (17.5 ml/kg, range 8-31 vs 21.0, range 15-30, P = 0.0001). Hematological recovery was faster in patients who received pre-treated BM (median time to PMN >0.5 x 10(9)/l and to platelets >20 x 10(9)/l was 12, range 10-14, and 13, range 10-18, days, respectively) than in those autotransplanted with steady-state BM (median time to PMN >0.5 x 10(9)/l and to platelets >20 x 10(9)/l 13, range 10-18 and 14, range 10-20 days, respectively, P = 0.004 and P = 0.01). Transfusional requirement was significantly different and patients of the G-CSF group needed shorter hospitalization (17 days, range 12-24, vs 20 days, range 14-32; P = 0.02). These data suggest that treating patients with G-CSF before BM harvest improves the quality of the harvest and accelerates engraftment and hematological recovery.     

Regeneration of peripheral blood cells following allogeneic bone marrow transplantation for severe aplastic anaemia

S ummary . We have studied the pattern of regeneration of peripheral blood cells following ABO compatible bone marrow transplantation for severe aplastic anaemia. 18 patients were treated with cyclosporin A and six with methotrexate for post graft immunosuppression. The number of days taken for the neutrophil count to reach 0.5 × 10⁹/l, the lymphocyte count to reach 1.0 x 10⁹/l, the platelet count to reach 100 × 10⁹/l and the reticulocytes to reach 1% was shorter in the CyA treated patients. This finding reached statistical significance for all types of cells except the platelets (neutrophils, P < 0.001; lymphocytes, P < 0.02; platelets, P > 0.05; reticulocytes, P < 0.001).     

Procalcitonin-reduced sensitivity and specificity in heavily leucopenic and immunosuppressed patients

Procalcitonin (PCT) has proven to be a very sensitive marker of sepsis for non-leucopenic patients. Little is known about its relevance in immunosuppressed and leucopenic adults. Four hundred and seventy-five PCT determinations were carried out in 73 haematological patients: on 221 occasions the white blood cell (WBC) count was < 1.0 x 10(9)/l and on 239 occasions it was > 1.0 x 10(9)/l leucocytes. Patients were classified as: non-systemic infected controls (n = 280), patients with bacteraemia (n = 32), sepsis (n = 30), severe sepsis (n = 3), septic shock (n = 3) and systemic inflammatory response syndrome (SIRS) (n = 62). When the WBC count was > 1.0 x 10(9)/l, gram-negative bacteria induced higher PCT levels (median 9.4 ng/ml) than gram-positives (median 1.4 ng/ml). In cases with a WBC < 1.0 x 10(9)/l, PCT levels were similar for gram-negative and gram-positive bacteria (1.1 ng/ml versus 0.85 ng/ml). Regardless of the leucocyte count, the median PCT level in bacteraemia cases always remained < 0.5 ng/ml. In heavily leucopenic situations, PCT levels were never > 2 ng/ml even in the sepsis and severe sepsis/septic shock groups, whereas a WBC count > 1.0 x 10(9)/l resulted in median PCT values of 4.1 ng/ml and 45 ng/ml respectively. The positive predictive value for sepsis (cut-off 2 ng/ml) was 93% in cases of WBC count > 1.0 x 10(9)/l, but only 66% in leucopenic conditions. The negative predictive value (cut-off 0.5 ng/ml) was 90% when the WBC count was > 1.0 x 10(9)/l and 63% in leucopenic conditions. Procalcitonin is an excellent sepsis marker with a high positive- and negative-predictive value in patients with WBC count > 1.0 x 10(9)/l, but it does not work satisfactorily below this leucocyte count.     

Gender and response to antilymphocyte globulin (ALG) for severe aplastic anaemia

We have evaluated the speed of haematological recovery in 103 severe aplastic anaemia (SAA) patients treated with antilymphocyte globulin (ALG) and followed at our institution for 3–15 years. We found that haemopoietic recovery was significantly delayed in six girls under the age of 10 years. This slow recovery in girls might be explained by their relative inability to release haemopoietic growth factors, granulocyte colony stimulating activity and burst promoting activity, compared to all other sex and age groups. This defect is not explained by disease severity at presentation and thus indicates a functional abnormality of monocytes/macro-phages and T-lymphocytes in addition to the deficiency of haemopoietic stem cells. In a multivariate analysis, low factor production and low pretreatment reticulocyte counts turned out to be strong predictors of slow haemopoietic recovery. We conclude that young girls have a particular form of SAA characterized by low haemopoietic factor production and delayed recovery after ALG. They are preferential candidates for early bone marrow transplantation or, if they are not eligible, for treatment with recombinant human haemopoietic growth factors.