A case report: Severe bone marrow suppression caused by 6-mercaptopurin in Crohn's disease patient]

A 23-year-old man was admitted for treatment of acute exacerbation of ileitis and perianal abscess caused by Crohn's disease. After incision and drainage of the abscess, coupled with antibiotic therapy, 6-mercaptopurine (6-MP) was commenced. His white blood cell (WBC) count on day 12 after initiation of 6-MP was not decreased. However, on day 24 he was re-admitted because of severe myelosuppression (WBC: 300/microl), which was complicated by the recurrence of the perianal abscess. Myelosuppression was prolonged and required the administration of granulocyte colony stimulating factor (G-CSF). G-CSF was continued for 17 days to achieve recovery of his WBC count to a normal level.     

A phase II trial of docetaxel for peripheral blood stem cell mobilization for patients with breast cancer and ovarian cancer

As docetaxel is known to have significant antineoplastic activity against breast and ovarian cancer, we explored its application as a peripheral blood stem cell mobilizing agent in 33 women with stage lll-IV ovarian carcinoma (n = 10) or stage ll-lV breast cancer (n = 23) who were in preparation for high-dose chemotherapy. Eleven patients had bone and/or bone marrow involvement with their disease. The median number of prior regimens received before mobilization was two (range 1-3). The three dose levels administered were 100 mg/m(2), 110 mg/m(2) and 120 mg/m(2). Patients received one dose of docetaxel in the outpatient setting followed by G-CSF (10 microg/kg/day) starting 4 days after docetaxel administration. Leukapheresis commenced when WBC >1.0 x 10(9)/l or when the WBC began to rise after reaching a nadir. Ninety-seven percent of patients began leukapheresis within 7-9 days after receiving docetaxel (range 7-10 days). The collection goal was >/=2 x 10(6) CD34(+) cells/kg. Twenty-seven (82%) patients reached this goal in a median of 2 leukapheresis days (range 1-3). No grade 2-4 nonhematologic toxicities were noted. Thirteen patients (55%) showed a WBC nadir >1.0 x 10(9)/l. None of the patients experienced neutropenic fever or required blood or platelet transfusion support. In conclusion, docetaxel + G-CSF is an effective, well-tolerated regimen for PBPC mobilization which can be safely administered in the outpatient setting with minimal toxicity.     

Automated collection of peripheral blood stem cells with the COBE spectra for autotransplantation

BACKGROUND: A convenient, effective and safe peripheral blood stem cell (PBSC) apheresis procedure is desirable to cope with the increasing requirements for PBSC collections. We performed PBSC harvesting with the novel COBE Spectra AutoPBSC(TM) system using the default software configuration recommended by the manufacturer. We analyzed collection parameters and clinical efficiency of harvested autografts following high-dose chemotherapy (HDCT). PATIENTS AND METHODS: Eighty-one patients underwent 102 harvests after standard chemotherapy plus filgrastim (5-10 microg/kg/day) to obtain a target of >/=2.5 x 10(6) CD34+ cells/kg for autologous blood stem cell transplantation. Conventional-volume leukaphereses (median: 11 liters) were performed using the manufacturer's standard software default regarding inlet flow, harvest/chase volume (3/7 ml) and number of collection cycles. The ratio of ACD-A to whole blood was initially set at 1:12 (56 collections), later at 1:10 (46 aphereses). RESULTS: With respect to preapheresis counts of 93 (9-876) CD34+ cells/microl, 69 patients (85.2%) achieved >/=2.5 x 10(6) CD34+ cells/kg by the first apheresis. PBSC products contained medians of 5.0 x 10(6) (0.7-77.3) CD34+ cells/kg and 13.8 x 10(4) (2.3-105.0) CFU-GM/kg. A preapheresis count of >/=40 CD34+ cells/microl predicted a single-apheresis yield of >/=2.5 x 10(6) CD34+ cells/kg. Apheresis products showed a high mononuclear cell (MNC) purity of >/=89%. The median overall collection efficiency of CD34+ cells (CD34-CE) was 42.6% (12.2-87.4). The CD34-CE decreased significantly with increasing numbers of circulating CD34+ cells: 52.5% at CD34+ cells <40/microl versus 41.0% at CD34+ cells >/=40/microl (p 0.5 x 10(3)/microl, 10 (8-13) days for WBC >1.0 x 10(3)/microl and 11 (8-17) days for platelets >20 x 10(3)/microl. CONCLUSIONS: As a result of efficient PBSC mobilization, a single conventional-volume leukapheresis with the COBE Spectra AutoPBSC system resulted in hematopoietic autografts with >/=2.5 x 10(6) CD34+ cells/kg in 85% of patients. Following the standard PBSC apheresis recommendations of the manufacturer, the AutoPBSC system assures PBSC products with a high MNC purity and a moderate CD34-CE that declines significantly at increasing levels of circulating CD34+ cells. Leukaphereses performed at an ACD-A to whole blood ratio of 1:10 should run without coagulation problems.     

Leukemoid reaction in association with bone marrow necrosis due to metastatic prostate cancer

An 80-year-old man presented to the internist with fever, fatigue and leukocytosis up to 66.8 x 10(3)/microl. Although a chronic myelogenous leukemia was initially suspected, he was diagnosed as metastatic bone marrow tumor with bone marrow necrosis from primary prostate cancer on the basis of the clinical and pathological findings. The serum concentrations of IL-6 and TNF-alpha were mildly elevated to 65.0 pg/ml and, 54.0 pg/ml respectively. It is probable that these humoral factors were partially responsible for the leukemoid reaction although other factors induced by the bone marrow necrosis with bone marrow metastasis of prostate cancer are also likely involved.     

Successful combined therapy with ATG, cyclosporin and G-CSF for both liver dysfunction and bone marrow failure in hepatitis-associated aplastic anemia]

A 28-year-old man developed cryptogenic hepatitis in January 1999, and treatment with glycyrrhizic acid improved his liver function. From June, however, pancytopenia began to develop gradually. The patient received G-CSF against leukocytopenia (WBC 1,100/microliter, neutrophils 590/microliter) and was transferred to our hospital in August 1999. A diagnosis of hepatitis-associated aplastic anemia was made on the basis of liver dysfunction (AST 156 IU/l, ALT 386 IU/l), hypoplastic bone marrow, and pancytopenia (WBC 4,400/microliter, neutrophils 3,340/microliter under G-CSF administration, Hb 9.8 g/dl, platelets 2.4 x 10(4)/microliter, reticulocytes 4.7 x 10(4)/microliter). Immediately after starting combined therapy with ATG, cyclosporin, and G-CSF, his liver function began to improve and was normalized on day 7. Pancytopenia began to ameliorate on day 9, and blood parameters on day 60 were WBC 4,200/microliter (without G-CSF administration), Hb 12.0 g/dl, platelets 9.0 x 10(4)/microliter, and reticulocytes 4.1 x 10(4)/microliter. Although the prognosis of hepatitis-associated aplastic anemia is generally poor, immunosuppressive therapy was markedly effective for both pancytopenia and hepatic dysfunction in the present case.     

Mobilization, harvesting and selection of peripheral blood stem cells in patients with autoimmune diseases undergoing autologous hematopoietic stem cell transplantation

Peripheral blood stem cells (PBSC) were mobilized in 130 patients with autoimmune diseases undergoing autologous hematopoietic stem cell transplantation using cyclophosphamide 2 g/m(2) and either granulocyte colony-stimulating factor (G-CSF) 5 mcg/kg/day (for systemic lupus erythematosus (SLE) and secondary progressive multiple sclerosis, SPMS) or G-CSF 10 mcg/kg/day (for relapsing remitting multiple sclerosis (RRMS), Crohn's disease (CD), systemic sclerosis (SSc), and other immune-mediated disorders). Mobilization-related mortality was 0.8% (one of 130) secondary to infection. Circulating peripheral blood (PB) CD34(+) cells/microl differed significantly by disease. Collected CD34(+) cells/kg/apheresis and overall collection efficiency was significantly better using Spectra apheresis device compared to the Fenwall CS3000 instrument. Patients with SLE and RRMS achieved the lowest and the highest CD34(+) cell yields, respectively. Ex vivo CD34(+) cell selection employing Isolex 300iv2.5 apparatus was significantly more efficient compared to CEPRATE CS device. Circulating PB CD34(+) cells/microl correlated positively with initial CD34(+) cells/kg/apheresis and enriched product CD34(+) cells/kg. Mean WBC and platelet engraftment (ANC>0.5 x 10(9)/l and platelet count >20 x 10(9)/l) occurred on days 9 and 11, respectively. Infused CD34(+) cell/kg dose showed significant direct correlation with faster white blood cell (WBC) and platelet engraftment. When adjusted for CD34(+) cell/kg dose, patients treated with a myeloablative regimen had significantly slower WBC and platelet recovery compared to non-myeloablative regimens.     

Recipients of HLA-identical sibling marrow transplants with severe aplastic anemia engraft more quickly, and those with chronic myeloid leukemia more slowly, than those with acute leukemia

An analysis of the rate of leukocyte reconstitution in 164 recipients of HLA-identical sibling marrow transplants showed two factors to be independently influential. These were the underlying diagnosis and the type of prophylactic regimen used to minimize the risk of graft-versus-host disease. Patients with severe aplastic anemia had a faster rate of reconstitution of the total white blood cell count to levels of both 500 and 1000 x 10(6)/l than patients with acute non-lymphoblastic leukemia (ANL), acute lymphoblastic leukemia (ALL) or chronic myeloid leukemia (CML). Patients with severe aplastic anemia (SAA), however, did not show a faster rate of reconstitution of blood neutrophils. As well as being slower than patients with SAA for total leukocyte reconstitution, patients with CML were slower than patients with ANL and ALL in attaining a neutrophil count of 500 x 10(6)/l, and slower than patients with ANL in attaining a neutrophil count of 1000 x 10(6)/l. Patients given cyclosporin as the sole immunosuppressant prophylactic regimen post-transplant had faster reconstitution to total leukocyte counts of 500 and 1000 x 10(6)/l and to neutrophils of 1000 x 10(6)/l than patients given methotrexate alone, methotrexate and cyclosporin, or cyclosporin and T cell depletion of the donor marrow. No other factors (including the pretransplant preparative regimen) were significant in influencing the rate of leukocyte or neutrophil reconstitution. When only patients given cyclosporin were analysed, those with severe aplastic anemia continued to show a faster rate of leukocyte reconstitution to WBC 500 x 10(6)/l compared to patients with ANL, ALL or CML, and a faster rate to WBC 1000 x 10(6)/l than patients with CML.(ABSTRACT TRUNCATED AT 250 WORDS)     

Successful high-dose methylprednisolone therapy in a patient with primary myelofibrosis

We are presenting a patient with primary myelofibrosis who responded to the High-Dose methylprednisolone therapy (1 g/day for 3 days). Three and a half years ago, a 55-year-old male was admitted to our hospital because of severe erythroblastic anemia, thrombocytopenia, splenomegaly and "dry tap" of bone marrow aspiration. Bone marrow biopsy revealed a marked fibrosis without any blastoid cell proliferations. Since a thrombocytopenia was progressive and refractory to the ordinary therapy, high-dose methylprednisolone therapy was performed which was followed by an administration of activated vitamin D3. After the therapy, hematologic improvements were achieved within a month (RBC: 284 x 10(4)/microliters----413 x 10(4)/microliters, WBC: 3,000/microliters----11,500/microliters, Plat.: 7,000/microliters----20,000/microliters). Three months after the therapy, the bone marrow biopsy and 113In scintigraphy were performed. These tests also proved marked improvement of histological features of the bone marrow and a decrease of uptake of 113In to the spleen, respectively. The patient continues to be in good condition and he is free from any medications at present time.     

Combination therapy with low-dose cyclosporin A, azathiopurine, and prednisolone for a child with refractory chronic idiopathic thrombocytopenic purpura

We report on a boy with refractory chronic idiopathic thrombocytopenic purpura (ITP) successfully treated with combination therapy composed of low-dose cyclosporin A (CsA), azathiopurine, and prednisolone. The patient was diagnosed as having ITP at 5 years of age, and received high-dose intravenous immunoglobulin (IVIG), followed by oral prednisolone, intravenous pulsed dexamethasone, oral cepharantin, and intermittent IVIG therapies. Because there were no or only transient responses to these medical therapies over 2 years, he was splenectomized. However, 3 months after the splenectomy, his platelet counts fell to below 10 x 10(3)/microl accompanied by wet purpura. We resumed low-dose intermittent IVIG treatment for 1 year without sustained efficacy. We then started combination therapy with CsA (2.5 mg/kg/day), azathiopurine (1.7 mg/kg/day), and prednisolone (0.8 mg/kg/day). Complete remission was achieved within 2 weeks and the platelet counts remained > 50 x 10(3)/microl even after tapering off the prednisolone and azathiopurine at 6 and 12 months, respectively and have moreover remained normal for more than 10 months after completion of 2 years of CsA treatment. There were no adverse events during the therapeutic course. This is the first pediatric case of ITP treated with CsA in Japan. Such combination therapy may be promising and tolerable for childhood ITP with splenectomy failure.     

Sustained long-term complete remission in an elderly aplastic anemia patient after cessation of combined therapy consisting of granulocyte-colony stimulating factor and erythropoietin

An 83-year-old woman received a diagnosis of moderate aplastic anemia in November 1990. Immunosuppressive therapy consisting of anti-lymphocyte globulin combined with high-dose corticosteroids was effective until pancytopenia developed in August 1993. The patient was hospitalized again and recurrence of aplastic anemia was diagnosed on the basis of hematologic findings, including RBC 129 x 10(4)/microliter, Hb 5.5 g/dl, Ret 23,200/microliter, WBC 2,200/microliter with 27% neutrophils, platelets 2.2 x 10(4)/microliter, and hypoplastic bone marrow. Recombinant human granulocyte-colony stimulating factor (G-CSF) of 125 micrograms/day combined with recombinant human erythropoietin (EPO) of 6,000 U/day were started in November 1993. The doses of G-CSF and EPO were increased to 250 micrograms/day and 12,000 U/day, respectively. We stopped combination therapy in March 1995, after trilineage hematopoietic cell recovery had been achieved. Complete recovery in peripheral blood was sustained for more than 2 years despite the termination of G-CSF and EPO therapy. Combination therapy with G-CSF and EPO may be safe and effective for elderly patients with aplastic anemia when the choice of therapy is limited.     

Myeloprotective effect of short-course high-dose methylprednisolone treatment before consolidation therapy in children with acute myeloblastic leukemia

In our previous studies, short-course high-dose methylprednisolone (HDMP) has been shown to shorten the chemotherapy-induced neutropenic period by stimulating the CD34(+) hematopoietic progenitor cells in children with acute leukemia. In this study, we investigate the role of short-course HDMP on induction of a myeloprotective effect when administered before consolidation therapy consisting of high-dose cytosine arabinoside and daunorubicin. Thirty-four consecutive newly diagnosed children with acute myeloblastic leukemia (AML) who received 64 courses of consolidation regimen were entered into the study. The patients received HDMP (group A) at a daily dose of 30 mg/kg methylprednisolone starting 4 days before the initiation of consolidation therapy. The control group did not receive HDMP (group B). There were no differences in the white blood cell (WBC) and absolute neutrophil counts (ANC) between group A (at day -4) and group B (at day 0) at the beginning of the study (medians: 3 x 10(9)/L vs. 3.2 x 10(9)/L and 1.5 x 10(9)/L vs. 1.7 x 10(9)/L, respectively). The WBC count increased significantly from 3 x 10(9)/L to 6.4 x 10(9)/L, and ANC increased from 1.5 x 10(9)/L to 3.9 x 10(9)/L after 4 days of HDMP treatment in group A (P < 0.01). Following high-dose chemotherapy, the median values of WBC and ANC also remained higher than the control values during the 16 days of the follow-up period. The neutropenic period was significantly shorter in the HDMP group than in the control group (9 +/- 5.2 days vs. 22 +/- 4.7 days) (P < 0.05). The duration of hospitalization and the interval between two chemotherapy cycles were significantly decreased in group A when compared group B (9 +/- 2.7 vs. 14 +/- 2.7 days; 22 +/- 4.7 vs. 26 +/- 4.2 days, respectively) (P < 0.05). Moreover, following consolidation therapy, the number of patients with ANC values below 0.5 x 10(9)/L was lower in group A when compared the group B. In conclusion, the administration of short-course (4 days) HDMP before high-dose chemotherapy has been found to be beneficial for reducing the duration and severity of neutropenia. Further studies with short-course HDMP are required to evaluate its myeloprotective effects in patients with other malignancies.     

Successful treatment with vincristine for an elderly patient with idiopathic thrombocytopenic purpura]

A 77-year-old female was referred to our hospital in March 1991 because of a severe bleeding tendency. Her blood count on admission was as follows: Hb 7.5 g/dl, WBC 4.6 x 10(9)/l with normal differentiation and platelet 2 x 10(9)/l. One month prior to admission, her blood count was normal. Initially, acute idiopathic thrombocytopenic purpura (ITP) was suspected, because of the acute onset of the bleeding tendency and thrombocytopenia. High dose intravenous immunoglobulin (400 mg/kg/day for 5 days) and bolus methylprednisolone (1 g/day for 3 days then tapered) were administered, starting March 13. Her platelet count had increased immediately on March 20 to 40 x 10(9)/l. However, platelet count decreased to 4 x 10(9)/l in the following two weeks. Her clinical course differed from that of typical acute ITP. Because the treatment with prednisolone was not effective, it was changed to intravenous infusion of vincristine (VCR) at a weekly dose of 1 mg for 6 weeks. The treatment was extremely effective, and her platelet count reached over 200 x 10(9)/l. The treatment was discontinued. Three weeks later, her platelet count decreased to 15 x 10(9)/l, the administration of VCR was resumed, and her platelet count recovered again. Throughout her clinical course, no side effect of VCR was noticed except for mild hypesthesia of the fingertips. VCR therapy was considered to be an useful treatment in elderly patients with ITP.     

Development of white blood cell fragments, during the preparation and storage of platelet concentrates, as measured by using real-time polymerase chain reaction

BACKGROUND AND OBJECTIVES: White blood cell (WBC) fragments may cause human leucocyte antigen (HLA) immunization in recipients. We investigated the occurrence and production of WBC fragments in platelet concentrates (PCs) and plasma units, during storage and filtration, by using real-time polymerase chain reaction (PCR) and flow cytometry. MATERIALS AND METHODS: To study the occurrence of WBC fragments, 'male' WBCs were spiked into double-filtered 'female' PCs in a concentration series of 0.03-100 WBCs/microl (n = 4 per level). To study the production of WBC fragments, 'male' WBCs were spiked into 'female' plasma units to 4 x 10(9) WBCs/l and stored at room temperature prior to filtration (n = 4 per storage time; t = 0, 24 or 48 h). DNA was measured by both albumin real-time PCR and Y real-time PCR. Intact WBCs were counted by using flow cytometry. The number of WBC fragments was calculated by subtracting cell-free DNA (real-time PCR on supernatant) and intact WBCs (flow cytometry) from the total DNA amount (real-time PCR). RESULTS: Spiking of 'male' WBCs into 'female' PCs showed that the Y real-time PCR is linear and has a reproducible quantitative range down to 0.03 WBC/microl, but that the albumin-PCR, in unspiked samples, revealed a total of 6-10 WBC equivalents/microl (eq/microl). After centrifugation, half of this was observed as cell-free DNA in the supernatant, suggesting that the remaining DNA is derived from WBC fragments. The number of intact WBCs, amount of cell-free DNA and number of WBC fragments after filtration increased significantly when filtration was delayed for up to 48 h, from 0.1 WBC/microl, 1.3 WBC eq/microl and 0.6 WBC eq/microl at t = 0 h to 25 WBC/microl, 38 WBC eq/microl and 57 WBC eq/microl at t = 48 h, respectively. CONCLUSIONS: WBC fragments occur in WBC-reduced PCs and increase when products are stored, prior to filtration, up to levels that are equivalent to the amounts of intact WBCs that induce HLA immunization (i.e. > 5 x 10(6)/unit).     

A phase II trial evaluating the safety and effectiveness of the AastromReplicell system for augmentation of low-dose blood stem cell transplantation

To reduce the number of apheresis procedures and maintain the usual rate of hematopoietic recovery in patients treated with high-dose chemotherapy, we studied the effect of adding a small volume of ex vivo expanded bone marrow to low doses of CD34(+) blood stem cells. Thirty-four patients with breast cancer received G-CSF (10 microg/kg/day) priming followed by a limited volume (50-100 ml) bone marrow aspiration and standard 10-liter aphereses. Marrow was expanded ex vivo using the AastromReplicell system and infused along with low doses of blood-derived CD34(+) cells, collected in one apheresis. Thirty-one evaluable patients received a median CD34(+) blood stem cell dose of 0.7 x 10(6)/kg (range, 0.2-2.5) and 4.7 x 10(7) nucleated cells/kg (range, 1.98-8.7) of ex vivo expanded marrow. All patients recovered with normal blood counts and engrafted 500 neutrophils/microl and 20 000 platelets/microl in a median of 10 and 13 days, respectively. Multivariate analysis revealed that, in addition to CD34(+) lineage negative cell quantity, the quantity of stromal progenitors contained in the ex vivo expanded product correlated with engraftment outcome (r = 0.551, P = 0.004). Our results indicate that ex vivo expanded bone marrow is capable of facilitating engraftment when combined with low doses of mobilized blood derived CD34(+) cells.     

抗人CD3T淋巴细胞单克隆抗体治疗重型再生障碍性贫血的初步观察

目的　探讨特异性免疫抑制剂鼠抗人CD3 T淋巴细胞单克隆抗体 (CD3 单抗 )对重型再生障碍性贫血 (SAA)的临床疗效。方法　 13例SAA患者中位数年龄 2 2岁 ,既往未经特殊治疗者4例 ,既往治疗无效的 9例中 ,加环孢素≥ 3个月者 4例 ;给药方法 :CD3 单抗 5mg静脉滴注 ,日 1次 ,连用 10d为一疗程。结果　共随访 3～ 15个月 ,骨髓象有 8例明显好转 ;外周血WBC平均升高 1 5 9× 10 9/L ,中性粒细胞升高 0 72× 10 9/L ,Hb升高 4 0 g/L ,血小板升高 4 7× 10 9/L(Р值均 <0 0 1) ;其中 2例基本治愈 ,2例达缓解 ,7例明显进步 ,2例无效 ;T淋巴细胞亚群的变化 :CD4/CD8比值由1 12± 0 34上升至 1 4 2± 0 4 3、HLA DR的表达率由 ( 2 9 2± 13 3) %下降至 ( 15 2± 5 6 ) % (Р值均<0 0 1) ;体外培养患者外周血单个核细胞分泌下列淋巴因子含量的中位数值 (U/ml) :肿瘤坏死因子α、干扰素γ与白细胞介素 2分别由 2 6 7、784和 92降至 15 2、5 70和 5 1(Р值均 <0 0 1)。不良反应 :单抗治疗期间 ,全部病例均有发热 ,4例出现胸闷、呼吸困难 ,但无 1例死亡。结论　与其他常用的免疫抑制剂相比 ,CD3 单抗对SAA的临床疗效更快、有效率可能更高 ,且安全性较好 ;关于该单抗的长期疗效、远期不良作用 ,有待于积累更多     

Current status and problem of platelet transfusion for hematopoietic diseases: results from a questionnaire survey

We carried out a survey on platelet transfusions performed in hospitals certified by the Japanese Society of Hematology. The average values of the pretransfusion platelet count (trigger value) for the day on which the transfusion was ordered, and the values on each day in the interval between the order and actual transfusion, were compared with the Guidelines. The average trigger value in aplastic anemia and myelodysplastic syndrome patients (A group) (1.41 x 10(4)/microl) for the same day on which the transfusion was ordered was higher than the Guideline, whereas those patients with hematological disorders undergoing chemotherapy (B group) and hematopoietic stem cell transplantation (C group), namely 2.08 x 10(4)/microl and 2.1 x 10(4)/microl, respectively, were acceptable values when compared with the Guidelines. On the other hand, in all groups, the transfusion trigger values at one or two days after ordering were higher than the Guidelines, being 2.56 x 10(4)/microl in the A group, 3.15 x 10(4)/microl in the B group, and 2.59 x 10(4)/microl in the C group. We have tried to formulate platelet count criteria for ordering a transfusion based on one day before the actual transfusion, because these platelet counts on ordering were relatively high. The criteria are 1.0-1.5 x 10(4)/microl in group A, 3.0 x 10(4)/microI in group B, and 3.0 x 10(4)/microl in group C. In order to perform platelet transfusion according to the Guidelines, the platelet count on ordering should be decreased as we proposed.     

Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group [see comments]

As curative bone marrow transplantation is available only to a minority of patients with chronic myelogenous leukemia (CML), drug therapy remains of central interest. Several nonrandomized studies have suggested that interferon-alpha (IFN) may prolong survival in CML. In a randomized multicenter study the influence of IFN versus busulfan or hydroxyurea (HU) on survival of Philadelphia-positive (Ph+) CML was examined. A total of 513 Ph+ patients were randomized for treatment as follows: 133 for IFN, 186 for busulfan, and 194 for HU. IFN-treated CML patients have a significant survival advantage over busulfan-treated (P = .008), but not over HU-treated patients (P = .44). The longer survival is due to slower progression to blast crisis. Median survival of IFN-treated patients is 5.5 years [5-year survival, 59%; 95% confidence interval (CI), 48%-70%], of busulfan-treated patients, 3.8 years (5-year survival, 32%; CI, 24%-40%), and of HU-treated patients, 4.7 years (5-year survival, 44%; CI, 36%-53%). Patients who continue on IFN survive longer than those in whom IFN is discontinued before blast crisis (P = .007). Complete hematologic IFN-responders have a survival advantage over partial responders or nonresponders (P = .02). Cytogenetic IFN-responders have no significant survival advantage over nonresponders (P = .2). Patients who attain white blood cell (WBC) counts of 10 x 10(9)/L or less have a survival advantage in the IFN (P = .007) and HU (P = .05) groups. Whereas toxicity in the IFN group was considerably higher than in the busulfan or HU groups, long-lasting cytopenias necessitating discontinuation of therapy as observed with busulfan have not been seen with IFN or HU. The problems of conventional prognostic scores (Sokal's score, Score 1) that we observed in IFN-treated patients support the idea that IFN changes the natural course of CML. We conclude that, with regard to survival of CML in the chronic phase, IFN is superior to busulfan and as effective as HU. Whether and to what extent IFN is superior to HU appears to depend, at least in part, on the degree of WBC suppression by HU-therapy and on the risk profile of the patients.