Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar)

A potential mechanism of chemotherapy resistance in acute myeloid leukemia (AML) is the multidrug resistance (MDR-1) gene product P-glycoprotein (P-gp), which is often overexpressed in myeloblasts from refractory or relapsed AML. In a multicenter phase II clinical trial, 37 patients with these poor risk forms of AML were treated with PSC 833 (Valspodar; Novartis Pharmaceutical Corporation, East Hanover, NJ), a potent inhibitor of the MDR-1 efflux pump, plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). Pharmacokinetic (PK) interactions of etoposide and mitoxantrone with PSC were anticipated, measured in comparison with historical controls without PSC, and showed a 57% decrease in etoposide clearance (P =.001) and a 1.8-fold longer beta half-life for mitoxantrone in plasma (P <.05). The doses of mitoxantrone and etoposide were substantially reduced to compensate for these interactions and clinical toxicity and in Cohort II were well tolerated at dose levels of 4 mg/m2 mitoxantrone, 40 mg/m2 etoposide, and 1 g/m2 C daily for 5 days. Overall, postchemotherapy marrow hypoplasia was achieved in 33 patients. Twelve patients (32%) achieved complete remission, four achieved partial remission, and 21 failed therapy. The PK observations correlated with enhanced toxicity. The probability of an infectious early death was 36% (4 of 11) in patients with high PK parameters for either drug versus 5% (1 of 20) in those with lower PK parameters (P =.04). P-gp function was assessed in 19 patients using rhodamine-123 efflux and its inhibition by PSC. The median percentage of blasts expressing P-gp was increased (49%) for leukemic cells with PSC-inhibitable rhodamine efflux compared with 17% in cases lacking PSC-inhibitable efflux (P =.004). PSC-MEC was relatively well tolerated in these patients with poor-risk AML, and had encouraging antileukemic effects. The Eastern Cooperative Oncology Group is currently testing this regimen versus standard MEC chemotherapy in a phase III trial, E2995, in a similar patient population.     

Pharmacology of cytarabine given as a continuous infusion followed by mitoxantrone with and without amsacrine/etoposide as reinduction chemotherapy for relapsed or refractory pediatric acute myeloid leukemia

The Ehrlichieae are gram-negative obligately intracellular bacterial pathogens. They can be divided into at least three genogroups on the basis of 16S rRNA gene sequences, but are also classified by target cell specificity. A group of granulocytic ehrlichiae primarily infect neutrophils and fall into genogroup II. The granulocytic ehrlichiae are subdivided by their target hosts, i.e., Ehrlichia phagocytophila in cattle and sheep, E. equi in horses, and the agents of human (HGE) and llama (LGE) granulocytic ehrlichioses. However, these subdivisions may give a false impression, as all these species are closely related both antigenically and on the basis of 16S rRNA operon sequence. In addition, cross-species transmission can occur naturally or by experimental infection. The vectors for these granulocytic ehrlichiae are hard-bodied ixodid ticks, and the reservoir hosts are probably wild rodents, deer and sheep. In each host, this illness presents as a febrile disease which can be followed by immunosuppression leading to secondary infections.     

Cytosine arabinoside and mitoxantrone induction chemotherapy followed by bone marrow transplantation or chemotherapy for relapsed or refractory pediatric acute myeloid leukemia

The purpose of this study was to determine the induction rate, duration of response and toxicity of cytosine arabinoside (1.0 gm/m2 i.v. over 2 h q 12 h x 8 doses days 1 through 4) and mitoxantrone (12 mg/m2 over 1 h daily x 4 doses days 3 through 6) in pediatric patients with acute myeloid leukemia (AML). Patients achieving a complete remission received either bone marrow transplantation or further chemotherapy. Twenty-seven of 37 evaluable patients (73% (95% confidence interval 59-87%)) achieved a complete remission. For all responding patients, the projected median time to relapse is 12 months. The projected 1 and 2 year disease-free survival is 47% (28-66) and 41% (21-61) with a range of follow-up of 0 to 48+ months. The major toxicity was bone marrow suppression and infection. This therapy is very active in pediatric AML and has acceptable toxicity. Some patients treated achieve prolonged survival.     

Reversal of multidrug resistance by SDZ PSC 833, combined with VAD (vincristine, doxorubicin, dexamethasone) in refractory multiple myeloma. A phase I study

SDZ PSC 833, a non-immunosuppressive cyclosporin analogue reverses multidrug resistance (MDR) in vitro by inhibiting P-glycoprotein (P-gp) mediated drug efflux. We performed a dose escalation study of SDZ PSC 833 combined with VAD chemotherapy in refractory multiple myeloma (MM). Twenty-two MM patients who were refractory to doxorubicin/vincristine/dexamethasone (VADr, n=11) or had failed multiple regimens (n=6) or were melphalan-refractory (MELr, n=5), were treated with one to three cycles of VAD combined with oral SDZ PSC 833, which was administered at escalating dosages starting at 5 mg/kg/day to 15 mg/kg/day for 7 days. The median trough and peak blood levels of SDZ PSC 833 ranged from 461/1134 ng/ml at 5 mg/kg/day to 821/2663 ng/ml at 15 mg/kg, respectively. With addition of SDZ PSC 833 (5 mg/kg) the mean plasma AUC 0-->96 h of doxorubicin as compared with control patients treated with VAD increased from 779 to 1510 ng/ml/h (P=0.0071), while the doxorubicin clearance was reduced from 47.6 to 27.8 l/h/m2 (P=0.0002). The clearance of doxorubicinol was reduced accordingly. Because of the increased plasma AUC, the dose of doxorubicin and vincristine had to be reduced in 13 patients to 50% (n=1) or 75% (n=12). A further dose-escalation of SDZ PSC 833 did not lead to a proportional increase of doxorubicin AUC. Toxicity WHO CTC grade 2 or 3 included hypoplasia (18/22), constipation (10/22), hyponatremia (3/22) and infections (6/22). A partial response or stable disease was achieved in eight and six patients, respectively. In 17 evaluable patients the mean percentage of pretreatment bone marrow plasma cells which expressed P-glycoprotein was 40%. The pretreatment in vitro rhodamin retention in CD38++ myeloma cells was reversible by 2 microM SDZ PSC 833 with 15-98% in 7/9 tested patients. In 4/5 responding patients analyzed before and after treatment with VAD + SDZ PSC 833, a reduction of P-gp + plasma cells was observed. It is concluded, that the blood concentrations of SDZ PSC 833 attained in MM patients increase with dose after oral administration. It can be safely combined with VAD chemotherapy. SDZ PSC 833 diminishes the clearance of doxorubicin, leading to an increase of the plasma AUC of doxorubicin. In addition, it is an effective inhibitor of P-gp mediated efflux of doxorubicin in myeloma tumor cells in vitro. Therefore, a proportional dose-reduction of doxorubicin and vincristine is warranted. Phase II/III studies in refractory MM are in progress to evaluate the therapeutic efficacy of SDZ PSC 833 with VAD.     

A phase II study of interleukin-2 in 49 patients with relapsed or refractory acute leukemia

Two monoclonal antibodies (mAb) within cluster M4 of the myeloid section of the Second International Swine CD Workshop, C4 (No. 144) and PM18-7 (No. 192), showed reactivity with thymocytes and among cells of myelomonocytic origin with mature macrophages but not with monocytes and granulocytes. Both mAb recognize a protein showing two bands of 205 kDa and 130 kDa under both reducing and non-reducing conditions. Although epitope mapping with these mAb could not be performed, this cluster received the SWC9 designation.     

Phase I trial of high-dose tamoxifen as a modulator of drug resistance in combination with daunorubicin in patients with relapsed or refractory acute leukemia

Tamoxifen and its main metabolite N-desmethyltamoxifen (NDMTmx) have been shown to increase intracellular daunorubicin (DNR) levels in human leukemia cell lines that display the multidrug resistant (MDR) phenotype. We designed a phase I dose escalation study of Tmx (200-700 mg/day p.o. for 7 days) in combination with a fixed dose of DNR (50 mg/m2 intravenously on days 5, 6 and 7) in patients with advanced leukemia to determine whether this combination could be given safely and whether plasma levels of 10 microM, the effective in vitro MDR modulator concentration, could be achieved. Pharmacologic studies of Tmx, NDMTmx and DNR, and its main metabolite daunorubicin-ol (DNR-ol) were performed as was determination of P-glycoprotein (Pgp) using a monoclonal antibody that recognizes an external epitope of the molecule. A total of 14 patients (median age 50, range 22-67) were treated at the following dose levels: 200 mg/day: three patients; 400 mg/day: four patients; 550 mg/day: three patients; and 700 mg/day: four patients. Two patients with relapsed AML achieved remission. Toxicity of the combination was similar to that seen with DNR alone and no severe hepatic, cardiac or retinal toxicity was noted. Plasma Tmx levels approached 7 microM at the two highest dose levels studied; plasma levels of NDMTmx were slightly less. The area under the curve for DNR and its main metabolite daunorubicin-ol (DNR-ol) did not show significant changes with escalation of Tmx dose. This phase I study suggests that concentrations of Tmx high enough to reverse the MDR phenotype can be approached and that the combination of high-dose Tmx with a standard dose of DNR has an acceptable toxicity profile. More evaluation in phase II studies is necessary to define further its role as an MDR modulator.     

Induction therapy for acute myelogenous leukemia in patients over 60 years with intermediate-dose cytosine arabinoside, mitoxantrone and etoposide

Using a broth microtiter dilution method, the minimum inhibitory concentrations of antipseudomonal antibiotics were determined against 19 P. aeruginosa isolates. Two different concentration of inoculum, 10(5) and 10(8), were used to show the inoculum concentration effect of in vitro antibiotic susceptibility tests. On the basis of the MIC values and using Howard B.J. (1) breakpoints, the effect of inoculum density was most prominent for amikacin and aztreonam, intermediate for mezlocillin, ticarcillin, piperacillin, cefotaxime, cefoperazone, netilmicin, tobramycin, gentamicin, and least apparent for ciprofloxacin and carbenicillin respectively.     

Evaluation of CI-973, a platinum analogue, in refractory or relapsed acute leukemia

Uranium isotopes were given via single intravenous injection into 22 young adult beagle dogs of both sexes to determine the metabolism of this element. Animals were given either 232U, 233U, 238U, or a combination of 232 (+) 233U. Calculations to assign a value of skeletal dose for each dog were performed using published radioactive properties of each uranium isotope and the metabolic data (including measured retention and skeletal distribution) derived from this study during a period of up to 2 y after injection. We believe that the procedures illustrated in this communication can serve as a useful pattern for estimating skeletal radiation doses to humans contaminated with 232U, 233U, or 238U.     

Bioavailability and phase II study of oral UFT plus leucovorin in patients with relapsed or refractory colorectal cancer

A summary of 733 reported cases of pancreatogastrostomy (PG) as a reconstructive procedure following pancreatoduodenectomy and the traumatically severed pancreas indicates an aggregate leakage rate of 4% over a 52-year period. Although mortality rates have declined over this period, the reported high correlation of leak with mortality seems to indicate the greater safety of PG over other methods for treating the residual pancreatic duct. The lower rate of complications related to pancreatocutaneous fistula from PG should correlate with shorter and less expensive hospital stays for patients treated with this technique. Several questions regarding technique must await further investigation.     

High-dose chemotherapy with carboplatin, etoposide and ifosfamide followed by autologous stem cell rescue in patients with relapsed or refractory malignant lymphomas: a phase I/II study

Patients with relapsed or refractory non-Hodgkin's lymphomas (NHL) and Hodgkin's disease (HD) with recurrences after an anthracyclin-containing regimen only have a chance of cure of below 10% with conventional chemotherapy. In order to improve their prognosis, we started a phase I/II trial using high-dose therapy comprising carboplatin, together with etoposide and ifosfamide (CEI), followed by autologous stem cell rescue (ASCR) as consolidation after salvage treatment. Since September 1990, 40 patients with intensively pretreated advanced NHL (n = 24) or HD (n = 16) received one cycle of high-dose therapy (HDT) consisting of carboplatin 1500 mg/m2, ifosfamide 10 g/m2 and etoposide in escalating doses from 1200 mg/m2 to 2400 mg/m2 followed by ASCR. Thirty-nine patients were assessable for toxicity and response. The following doses appeared to be safe: carboplatin 1500 mg/m2, etoposide 2400 mg/m2 and ifosfamide 10 g/m2. All patients developed grade 3 nausea and grade 3 or 4 mucositis. Granulocytopenic fever occurred in 100% with grade 4 infections in 15%. Mild transient kidney toxicity was noted in 36% and liver toxicity in 20% of patients. One toxic death occurred (2.5%). Objective responses were obtained in 36 of 39 patients (92%) with complete remissions (CR) in 24 patients (61.5%) and partial remissions (PR) in 12 (30.7%). Median observation time for surviving patients was 23.3 months (range 3.4-52.3). The probabilities of overall, event-free and relapse-free survival at 2 years are 62, 39 and 55%, respectively. Patients with primary refractory disease or resistant relapse had a poor prognosis. High-dose carboplatin, etoposide and ifosfamide plus autologous stem cell rescue represents an effective, potentially curative salvage treatment with acceptable toxicities.     

Low-dose total body irradiation and G-CSF without hematopoietic stem cell support in the treatment of relapsed or refractory acute myelogenous leukemia (AML), or AML in second or subsequent remission

PURPOSE: Patients with relapsed acute myelogenous leukemia (AML), who are not eligible for bone marrow transplantation, have a poor prognosis when treated with chemotherapy alone. Total body irradiation (TBI) is an effective modality against AML when used in doses of 1000-1400 cGy with hematopoietic stem cell support. We undertook a phase I study of TBI with granulocyte-colony-stimulating factor (G-CSF) support, without stem cell support in patients with AML either in relapse or second or subsequent remission. METHODS AND MATERIALS: Patients with relapsed AML, or AML in second or subsequent remission were treated in a phase I study of TBI followed by G-CSF. The first dose level was 200 cGy. After the initial cohort of patients it was clear that patients with overt leukemia did not benefit from this treatment, and subsequent patients were required to be in remission at the time of TBI. RESULTS: Eleven patients were treated, 4 in overt relapse, and 7 in remission. 200 cGy was used in all, and dose escalation was not possible due to prolonged thrombocytopenia in all patients but one. Neutrophil recovery was adequate in those patients who remained in remission after TBI. Patients with overt leukemia had transient reduction in blast counts, but rapid recurrence of their leukemia. Patients treated in remission had short remissions, with the exception of one patient who is in remission 32 months after treatment. CONCLUSION: There is some antileukemic effect of TBI even at 200 cGy, though this dose appears to be too low to help a significant number of patients. If TBI is to be escalated without stem cell support, then a thrombopoietic agent will need to be used.     

Phase II study of recombinant interleukin 1alpha and etoposide in patients with relapsed osteosarcoma

A Phase II trial using interleukin 1alpha (IL-1alpha) and etoposide for patients with relapsed osteosarcoma (OS) was undertaken to assess the feasibility and tolerability of combination therapy with biotherapy and chemotherapy. Nine patients with histologically proven relapsed OS were treated with IL-1alpha immediately followed by etoposide daily for 5 days every 3 weeks. Surgical resection of lung metastasis or peripheral tumor was performed after two or three cycles. We observed three partial responses; disease was stable in another case. One case could not be evaluated. The side effects associated with combination therapy were as predicted from known side effects of the individual agents; however, more profound neutropenia was observed. Four patients exhibited clinical signs of capillary leak syndrome, i.e., hypotension, edema, and weight gain. The etiology of the capillary leak was unclear, because serum IL-1alpha, IL-2, tumor necrosis factor, and nitric oxide levels could not be used to predict which patients would develop capillary leak. Histological analysis of tumor specimens obtained after two or more courses of therapy showed changes consistent with a response to a biological response modifier: peripheral fibrosis surrounded the metastasis with infiltration of chronic and acute inflammatory cells. Because the response of relapsed OS to any type of salvage regimen has been poor, we interpret the clinical response of this therapy as good. However, the significant side effects associated with this therapy must also be taken into consideration before deciding to use this combination therapy. It is unfortunate that the study was stopped early due to halted production of IL-1alpha. If this agent is again manufactured for clinical use, we conclude that additional evaluation in patients with relapsed OS is warranted.     

A phase II study with high-dose cytarabine (NS-075) in adult patients with relapsed and refractory acute leukemia

A multi-center phase II clinical study with high dose cytarabine (NS-075) was conducted in adult patients with relapsed and/or refractory acute leukemia. 2 g/m2 cytarabine was given 12 times by 3-hour intravenous infusion every 12 hrs. 46 patients were registered, and 44 were evaluable: 35 with acute myeloid leukemia (AML) and 9 with acute lymphoblastic leukemia (ALL). There were 28 males and 16 females, with a median age of 37.5 years (range 15-68), including 6 of more than 60 years. Among 35 patients with AML, there were 16 (45.7%) complete and 2 (5.7%) partial remissions. Among 9 patients with ALL, there were 2 (22.2%) complete and 1 (11.1%) partial remissions. The major non-hematologic toxicities were gastrointestinal symptoms such as nausea/vomiting, anorexia and diarrhea, as well as fever, infection, conjunctivitis, alopecia, hepatic and renal dysfunctions. Central nervous system (CNS) toxicity was mild and reversible. Therapy-related death occurred in 5 patients resulting from prolonged pancytopenia, which suggests the necessity of strict countermeasures for infections as well as good patient care. These results indicate that high-dose cytarabine is a promising therapy for treatment of relapsed and/or refractory acute leukemia.     

Pulmonary insufficiency complicating therapy with high dose cytosine arabinoside in five pediatric patients with relapsed acute myelogenous leukemia

BACKGROUND: The occurrence of fatal or nearly fatal pulmonary insufficiency in 5 of 22 pediatric patients with relapsed acute myelogenous leukemia (AML) treated with high dose cytosine arabinoside (Ara-C) at St. Jude Children's Research Hospital, Memphis, Tennessee, and institutions affiliated with the Pediatric Oncology Group (POG) is reported. METHODS: Cytosine arabinoside (1.0-1.5 g/m2/day) was given as a 5-day continuous infusion to all patients. Four patients with persistent leukemia received a second 3- or 5-day course. The POG protocol included the administration of granulocyte colony stimulating factor for the priming of myeloblasts. Diagnostic criteria for pulmonary insufficiency included noncardiogenic pulmonary edema with exclusion of underlying cardiorespiratory, infectious, or metabolic conditions. Autopsy material also was reviewed. RESULTS: Of the 22 patients 5 died (23%), including 2 who received a second course of Ara-C as a result of pulmonary insufficiency that developed at a median of 8 days (range, 3-38 days) after the first course. Three patients died despite intubation and pressor support. Two patients were managed successfully with colloids, diuresis, and oxygen by face mask; remission was achieved in both. The postmortem examination of one patient disclosed airless lungs, profound pulmonary edema, and subpleural nodules, but no evidence of leukemia. CONCLUSION: Pulmonary insufficiency from high dose Ara-C varies in severity and may be fatal. It may occur during or after treatment. Awareness of this potential complication, careful attention to fluid status, and aggressive supportive care may optimize outcome.     

A phase I study of recombinant human soluble interleukin-1 receptor (rhu IL-1R) in patients with relapsed and refractory acute myeloid leukemia

PURPOSE: The recombinant human interleukin-1 receptor (rhu IL-1R) is a soluble truncated form of the type 1 full-length membrane-bound receptor that binds IL-1 with identical affinity to that of the membrane form. As such, it may have clinical potential by sequestering IL-1, thereby preventing it from binding to its membrane-bound receptor and eliciting a biological effect. As IL-1 has been shown to regulate leukemic cell proliferation in an autocrine fashion, a phase I trial of rhu IL-1R was conducted in patients with relapsed and refractory acute myeloid leukemia (AML). METHODS: The study group comprised 11 patients who were sequentially treated on one of three dose levels, receiving a single intravenous (i.v.) bolus dose on day 1 followed by 13 days of daily subcutaneous (s.c.) injections with the option of an additional 14 days of treatment if a response of stable disease or better was achieved. Dose level 1 i.v. bolus 500 microg/m2, s.c. dose 250 microg/m2 per day (five patients); dose level 2 i.v. bolus 1000 microg/m2, s.c. dose 500 microg/m2 per day (three patients); dose level 3 i.v. bolus 2000 microg/m2, s.c. dose 1000 microg/m2 per day (three patients). Owing to limited drug availability, the study was designed to only examine these three dose levels. RESULTS: rhu IL-IR was well tolerated. There was no grade 3 or 4 non-hematological toxicity related to the study drug and the maximum tolerated dose was not reached. No IL-1R-blocking antibodies developed during the course of the study. Serum levels of IL-1beta, IL-6 and TNF were undetectable before, during and after rhu IL-IR administration. The terminal half-life after i.v. dosing was at least 7-12 h, and after s.c. dosing 2-4 days. Serum levels of rhu IL-1R up to 360- and 25-fold those of pretreatment levels were achieved after i.v. and s.c. dosing respectively. No patient had a complete, partial or minor response to treatment; four had stable disease and seven had progressive disease. CONCLUSIONS: rhu IL-1R therapy was safe but did not have any apparent antileukemic effect at the doses administered.     

Low-dose oral etoposide and subcutaneous injection of low-dose cytosine arabinoside (Et-A non i.v.) with or without minimum anthracycline for refractory acute non-lymphoblastic leukemia

Low-dose oral etoposide (50 mg for 10 to 14 days) and low-dose subcutaneous injection of cytosine arabinoside (15-20 mg/12 hours for 14 to 17 days) (Et-A non i.v.) were given to refractory acute non-lymphoblastic leukemia patients. Case 1 was a 47-year-old woman who had a relapsed M0. B-DOMP therapy failed but she recovered from severe infection. She had to go home to take care of her children. Et-A non i.v. was given for 14 days and 11 mg of mitoxantrone was added on the 3rd day. She achieved a complete remission (CR). Case 2 was a 72-year-old woman classified M4. Low-dose cytosine arabinoside (Ara-C) with additional daunorubicin (DNR) therapy failed. She became weaker due to the gastrointestinal toxicity of DNR. Et-A non i.v. was tried. Oral etoposide (Et) for 10 days and Ara-C for 14 days proved effective, and she achieved CR. Case 3 was a 59-year-old man with M4 developed from myelodysplastic syndrome, complicated with infection. Ara-C low-dose therapy was begun, but it was not effective. It was switched to Et-A non i.v., 40 mg of DNR was added, with 12 mg of mitoxantrone and double administration of 3 mg of vindesine. He also achieved CR. Et-A non i.v. therapy is effective and available for induction therapy with low toxicity and convenient to daily life.     

雷公藤红素体外抑制人类急性髓系白血病细胞的实验研究

目的 研究雷公藤红素体外对人类急性髓系白血病(AML)细胞的体外抑制作用.方法 应用四甲基偶氮唑蓝(MTT)法和流式细胞术(FCM)等方法研究雷公藤红素对人类AML细胞的影响.结果 MTT实验显示,与空白组比较,培养不同时间后不同浓度组雷公藤红素的细胞增殖抑制率均明显升高,差异有统计学意义(P＜0.01).FCM检测结果显示,1 μmol/L以上浓度雷公藤红素作用不同时间,AML细胞均可出现凋亡现象,凋亡率明显高于不加药物的对照组(P＜0.01).结论 雷公藤红素对AML有明显的抑制作用,其作用可能与其诱导细胞凋亡有关.     

硼替佐米治疗复发难治性套细胞淋巴瘤的研究进展

复发难治性套细胞淋巴瘤(MCL)的治疗是临床医师面临的严峻挑战.近年来,蛋白酶体抑制剂硼替佐米的应用给复发难治性MCL患者的治疗提供了新方法.就硼替佐米治疗复发难治性MCL的机制、临床疗效以及MCL细胞对硼替佐米耐药产生的机制和应对策略进行综述.     

Bone marrow transplantation for children less than 2 years of age with acute myelogenous leukemia or myelodysplastic syndrome

We analyzed results of 40 infants less than 2 years of age who received bone marrow transplants (BMT) between May 1974 and January 1995 for treatment of acute myelogenous leukemia (AML; N = 34) or myelodysplastic syndrome (MDS; N = 6) to determine outcome and survival performance. Among the AML patients, 13 were in first remission, 9 were in untreated first relapse or second remission, and 12 were in refractory relapse. Patients were conditioned with cyclophosphamide in combination with either total body irradiation (TBI; N = 29) or busulfan (N = 11). Source of stem cells included 6 autologous donors, 15 HLA genotypically identical siblings, 14 haploidentical family members, and 5 unrelated donors. Graft-versus-host disease (GVHD) prophylaxis was methotrexate (MTX) for 17, MTX plus cyclosporine (CSP) for 14, or CSP plus prednisone for 3. Incidence of severe (grade 3-4) regimen-related toxicity was 10% and transplant-related mortality was 10%. Acute GVHD (grades II-III) occurred in 39% of allogeneic patients, and chronic GVHD developed in 40%. Relapse, the most significant problem for patients in this study, occurred in 1 MDS patient and 23 AML patients and was the cause of death for 19 patients. The 2-year probabilities of relapse are 46%, 67%, and 92%, respectively, for patients transplanted in first remission, untreated first relapse or second remission, and relapse. One MDS and 8 AML patients received second marrow transplants for treatment of relapse, and 5 of these survive disease-free for more than 1.5 years. All 6 MDS patients and 11 of 34 AML patients survive more than 1.5 years later. The 5-year probabilities of survival and disease-free survival are 54% and 38% for patients transplanted in first remission and 33% and 22% for untreated first relapse or second remission. None of the patients transplanted with refractory relapse survive disease-free. Outcome was significantly associated with phase of disease at transplantation and pretransplant diagnosis of extramedullary disease. Long-term sequelae included growth failure and hormonal deficiencies. Survival performance was a median of 100% (80% to 100%) and neurologic development for all survivors was appropriate for age. This study indicates that infants with AML have similar outcome after BMT compared with older children and that BMT should be performed in first remission whenever possible. In addition, allogeneic BMT provides effective therapy for the majority of infants with MDS.