Combination of liposomal daunorubicin (DaunoXome), fludarabine, and cytarabine (FLAD) in patients with poor-risk acute leukemia

Sixty-two patients with high-risk acute leukemia were treated with the FLAD regimen [3 days of treatment with fludarabine 30 mg/m², cytarabine (AraC) 2 g/m², and liposomal daunorubicin 80 mg/m²]. The acute myeloid leukemia (AML) patients were either refractory to standard induction regimens (8), were in first or second relapse (13), or received therapy as first-line treatment [21 patients, 16 were above 60 years of age and 5 had post-myelodysplastic syndrome (MDS) AML]. The acute lymphoblastic leukemia (ALL) patients were treated for relapsed (7) or refractory disease (10). Three patients had chronic myeloid leukemia (CML) in the blastic phase. FLAD was well tolerated by most patients. Ten major infectious complications were recorded while no signs of cardiac toxicity were observed. Five patients (8%) died before day 28 with hypocellular marrow, mainly of infection or hemorrhage, and response could not be evaluated. Complete response rate was 62% and 69% among AML patients treated at diagnosis or for relapsed disease, respectively, and 59% among the ALL patients. Furthermore, FLAD managed to overcome the negative impact of poor prognosis karyotype in ALL patients, since five of the seven patients with t(9;22) or complex karyotype achieved complete remission (CR). Nine patients underwent bone marrow transplantation (BMT). Among the AML patients who were treated at diagnosis or for relapse, the median duration of CR was 7 months (range: 2–18) and 8 months (range: 2–26), respectively. Median survival among these patients was 8 (range: 1–40) and 12 (range: 1–30) months, respectively. Similar values were found in ALL patients. In conclusion, FLAD may be an effective alternative treatment for patients with relapsed AML and for patients with ALL who failed first-line therapy.     

Successful treatment of hepatosplenic candidiasis in an elderly patient with acute myeloid leukemia using liposomal daunorubicin and fluconazole

Fungal infections are an increasing cause of morbidity and mortality in patients with haematological malignancies. The organism most often responsible are Candida spp., particurarly Candida Albicans. This report describes our experience in a 63-year-old man who developed symptoms of hepatosplenic candidiasis caused by Candida tropicalis after treatment for acute myeloid leukaemia (AML). The fungal infection was successfully controlled using fluconazole, and the patient has been disease-free for more than 11 months after antileukemic chemotherapy without any recurrence of Candida infections. Our experience suggests that AML and chemotherapy associated fungal infections can be controlled with an appropriate therapeutic regimen.     

Escalated daunorubicin dosing as an induction treatment for Philadelphia-negative adult acute lymphoblastic leukemia

The dose intensity of daunorubicin (DNR) delivered during the induction period represented the major prognostic factor for the outcome of adult acute lymphoblastic leukemia (ALL). The aim of this study was to determine the survival or toxicity of escalated doses of DNR in induction treatment of adult patients with acute lymphoblastic leukemia who are at least 15 years of age. For induction chemotherapy, all patients were given 90 mg/m²/day of DNR by continuous intravenous (IV) infusion over 24 h daily on days 1–3, 2 mg of vincristine IV push on days 1 and 8, and 60 mg/m²/day of prednisolone per oral (PO) on days 1–14 in conjunction with 4,000 units/m²/day of l-asparaginase intramuscular or subcutaneous on days 17–28. The median patient age was 32 years (range, 15–69). Complete remission (CR) was achieved in 169 (88.5 %) patients, while 4 died before CR was reached. Additionally, 11 patients died from leukemia progression, 4 had refractory disease, and 3 had follow-up loss. The median follow-up time was 697 days (range, 12–2,270). The 3-year cumulative incidence of relapse was 49.3 %. The probabilities of disease-free survival and overall survival at 3 years were 46.1 and 43.1 %, respectively. The dose of DNR was 100 % of the target dose, and there were no additional specific toxicities. The results show that escalated doses of DNR in induction chemotherapy are similar with the standard dose in response and toxicities. Our study indicates that a more effective regimen or better chemotherapy agents are needed to improve the CR rate and prolong survival in Philadelphia-negative adult ALL.     

A comparison of the in vitro cytotoxicity of daunorubicin and liposomal daunorubicin in pediatric acute leukemia

Anthracyclines are effective in the treatment of leukemia, but their use is limited because of cardiotoxicity. Liposomal daunorubicin (L-DNR) is potentially less cardiotoxic than daunorubicin (DNR). We compared in vitro cytotoxicity in pediatric acute leukemia samples and found no significant differences between cytotoxicity of DNR and L-DNR.     

High-dose methotrexate in the treatment of adult acute lymphoblastic leukemia

 The application of high-dose treatment elements has an increasing importance in the therapy of acute lymphoblastic leukemia (ALL). High-dose methotrexate (HDMTX) has been introduced in clinical trials more than 20 years ago, since it has several theoretical advantages compared to conventional dose methotrexate. These trials revealed that the efficacy and toxicity of HDMTX depends on features such as dose level, infusion time, combination regimen and schedule of leucovorin rescue. Particularly the application of controlled leucovorin rescue and improved supportive care enabled the application of increasing doses of HDMTX in the treatment of childhood and adult ALL within a variety of schedules and at dose levels mostly ranging between 0.5 g/m² and 5.0 g/m². In childhood ALL, first devised to replace CNS irradiation in the prophylaxis of CNS relapse HDMTX has contributed to the reduction of bone marrow relapses particularly in low risk B-lineage ALL. In addition it proved to be an effective therapy element for prophylaxis and treatment of CNS disease. At least in low risk ALL CNS irradiation could be safely replaced by repeated cycles of HDMTX with additional intrathecal therapy. In adult ALL only few of the succesful treatment approaches with HDMTX have been investigated up to now. The results indicate that HDMTX has a beneficial effect with regard to overall outcome in adult B-lineage ALL. It provides effective CNS prophylaxis in combination with intrathecal therapy. In mature B-ALL HDMTX proved to be one of the most effective treatment elements and contributed to an impressive improvement of outcome in this subgroup. For T-ALL however sufficient data do not exist either in childhood or in adult ALL. Since HDMTX is an effective treatment element with manageable acute and long-term toxicity, its role in the management of adult ALL should be explored more intensively. Received: 15 January 1996 / Accepted: 17 January 1996     

Sequential continuous infusion of fludarabine and cytarabine associated with liposomal daunorubicin (DaunoXome) (FLAD) in primary refractory or relapsed adult acute myeloid leukemia patients

A large proportion of adult patients with acute myeloid leukemia (AML) relapse after treatment, and some of them are resistant to primary induction chemotherapy. Sixty-one patients from seven hematological centers with poor-risk AML, primary refractory (n = 16), or relapsed (n = 45) were treated with a salvage regimen, including fludarabine (2 days) and cytarabine (3 days) in a sequential continuous infusion, associated with liposomal daunorubicin (3 days) (FLAD). Complete response rate was 44% and 56% for refractory and relapsed patients, respectively, with an overall response rate of 52% (32 of 61). Twenty-two patients (36%) were resistant to the salvage therapy. Seven patients (12%) died early during chemotherapy, four of them because of sepsis. Nineteen patients in complete remission (CR) underwent a stem-cell transplant (SCT) procedure: five autologous, nine from a HL-A identical sibling, and five from HL-A matched unrelated donors. Post-treatment aplasia and mucositis were major toxicities. Twenty patients (62.5%) relapsed after this treatment in a median of 7.3 months; ten patients relapsed after a SCT procedure. Nine patients are alive and disease free; three of them were rescued after a further cytotoxic treatment. The FLAD regimen proved to be an effective and well-tolerated treatment, with acceptable toxicity in this group of high-risk patients. A better response rate was obtained in the subgroup of relapsed patients, compared to patients treated for refractory disease. More then half (five of nine) of long-surviving patients are those who were submitted to a transplant procedure; thus, the main indication for FLAD seems to be to try to induce a rapid CR with minimum toxicity in order to perform a transplant as soon as possible.     

High-dose cytosine arabinoside and daunorubicin postremission therapy in adults with de novo acute myeloid leukemia

A total of 149 consecutive de novo AML patients aged 50 years or less (median age = 37 years) were enrolled in this prospective multicenter trial initiated in May 1985. All patients received the same induction and early consolidation therapy with daunorubicin (DNR), cytosine arabinoside (Ara-C), and etoposide (DAV). High-dose Ara-C/DNR therapy included Ara-C at 3 g/m², in 12 doses (HD-Ara-C/DNR I) and eight doses (HD-Ara-C/DNR II), followed by DNR 30 mg/m² for 3 days. A complete remission (CR) was achieved in 104 (70%) patients; 61 complete responders received at least one cycle with HD-Ara-C/DNR. If those patients who were transplanted in first CR (n=26), were not considered, the median relapsefree-survival (MRFS) of the remaining 78 patients was 15 months, with a probability of relapse-free survival (RFS) at 116 months of 30% (95% CI, 20–40%) after a median follow-up of 95 months. The MRFS of the HD-Ara-C/DNR consolidated patients was 25 months, with a probability of RFS at 116 months of 37% (95% CI, 24–50%). If all patients who were transplanted (n=44) were not considered, the median survival time (MST) was 18 months with a probability of being alive at 118 months of 24% (95% CI, 16–33%). MST of the HD-Ara-C/DNR consolidated patients was 58 months with a survival probability of 46% (95% CI, 31–60%) at 118 months. Prognostic factor analysis did not reveal any significant influence of age, sex, FAB subtype, white blood cell count, hemoglobin level, thrombocyte count, LDH, or response to the first induction course on RFS of the HD-Ara-C/DNR consolidated patients. In summary, HD-Ara-C/DNR consolidation can improve the long-term outcome of a subgroup of de novo AML patients. Further improvement of the outcome seems to depend on the identification of patients with an inferior outcome under that strategy who might benefit from alternative treatment strategies.     

Phase 2 study of hyper-CMAD with liposomal vincristine for patients with newly diagnosed acute lymphoblastic leukemia

Liposomal vincristine is designed to reduce neurotoxicity and increase dose intensity delivery, and has been approved as salvage therapy in relapsed/refractory acute lymphoblastic leukemia (ALL). Our aim was to evaluate the response rate, toxicities, and outcome of adults with newly diagnosed ALL who received liposomal vincristine, rather than regular vincristine in combination with intensive chemotherapy (Hyper-CMAD). In a single-center, phase 2 study, patients ≥18 years with newly-diagnosed B-cell ALL were eligible to receive hyper-CMAD alternating with high-dose methotrexate and cytarabine. Rituximab was administered in CD20 positive ALL. Tyrosine kinase inhibitors (imatinib or dasatinib) were added in Philadelphia chromosome-positive (Ph-positive) ALL. Thirty-one patients were enrolled, median follow-up of 59 months (0.3-70). Thirteen patients (42%) had CD20 positive ALL, and 21 (68%) had Ph-positive ALL. Thirty (97%) achieved complete remission (CR). All 26 patients with abnormal karyotype achieved complete cytogenetic response (CCyR), and 27/30 (90%) achieved negative minimal residual disease status by multicolor flow cytometry. Of 20 evaluable Ph-positive ALL patients, major molecular response (MMR) was achieved in 19 patients (95%); complete molecular response (CMR) in 14 (70%). Grade 3/4 peripheral neuropathy was observed in five (16%) with all grade peripheral neuropathy in 21 (68%). With a median follow-up of 59 months, 21 (68%) patients are alive. The 5-year CR duration and survival rates were 73% and 61%, respectively. Ten (32%) patients died: one, sepsis on C1D10; four, unknown; one, post-transplant complications; four, relapse. Hyper-CMAD with liposomal vincristine is safe and demonstrated high response and survival rates in newly diagnosed ALL.     

A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia: the GRAALL-SA1 study

Background

The prognosis of acute lymphoblastic leukemia in the elderly is poor. The GRAALL-SA1 phase II, randomized trial compared the efficacy and toxicity of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in patients 55 years or older with Philadelphia chromosome-negative acute lymphoblastic leukemia.

Design and Methods

Sixty patients received either continuous-infusion doxorubicin (12 mg/m²/day) and continuous-infusion vincristine (0.4 mg/day) on days 1–4 or pegylated liposomal doxorubicin (40 mg/m²) and standard vincristine (2 mg) on day 1, accompanied by dexamethasone, followed at day 28 by a second cycle, reinforced by cyclophosphamide. End-points were safety, outcome and prognostic factors.

Results

Myelosuppression was reduced in the pegylated liposomal doxorubicin arm with shorter severe neutropenia (P=0.05), shorter severe thrombocytopenia (P=0.03), and fewer red blood cell transfusions (P=0.04). Grade 3/4 infections and Gram-negative bacteremia were reduced in the pegylated liposomal doxorubicin arm (P=0.04 and P=0.02, respectively). There was a trend towards fewer cardiac events among the patients who received pegylated liposomal doxorubicin (1/29 versus 6/31). The complete remission rate was 82% and, with a median follow-up of 4 years, median event-free survival and overall survival were 9 and 10 months, respectively. Despite the better tolerance of pegylated liposomal doxorubicin, no differences in survival were observed between the two arms, due to trends towards more induction refractoriness (17 versus 3%, P=0.10) and a higher cumulative incidence of relapse (52% versus 32% at 2 years, P=0.20) in the pegylated liposomal doxorubicin arm.

Conclusions

With the drug schedules used in this study, pegylated liposomal doxorubicin did not improve the outcome of elderly patients with acute lymphoblastic leukemia despite reduced toxicities.     

High-dose methylprednisolone for children with acute lymphoblastic leukemia and unfavorable presenting features

Abstract: In an attempt to improve treatment outcome high-dose methylprednisolone (HDMP, 20–30 mg/kg, once a day orally) was used instead of a conventional dose of steroid (2 mg/kg/d, in 3 divided doses) in children with acute lymphoblastic leukemia (ALL) with increased risk factors. HDMP combined with cytotoxic agents (vincristine and l -asparaginase) resulted in an improved complete remission rate (94%) in 48 newly diagnosed children with ALL compared to 81% in 86 historical controls receiving standard dose steroid combined with the same treatment regimen. The bone marrow relapse rate was lower in patients who received HDMP (31%) than in controls (56%). Treatment was discontinued in 56% of 48 patients receiving HDMP and in 35% of 86 controls. The difference was significant (p<0.05). The 5-yr continuous complete remission rate was significantly greater in patients received HDMP compared with the control patients (60% vs. 43%, p<0.05). HDMP treatment was well tolerated without significant adverse effects. Moreover, during induction therapy the duration of leukopenia (< 2 × 10⁹/L) was shorter in patients receiving HDMP. We conclude that HDMP combined with other antileukemic agents increased the CR rate and prolonged the duration of remission in children with ALL who had increased risk factors. However, the optimal dosage of HDMP and its role in maintenance therapy should be determined in future, randomized studies.     

Sequential therapy with daunorubicin and L-asparaginase in relapses of acute lymphoblastic leukemia in children.

13 children affected by acute lymphoblastic leukemia in advanced stage of illness received a sequential therapy with daunorubicin and L-asparaginase. During daunorubicin therapy a significant decrease of bone hypercellularity as well as circulating cells occurred, a further cycle with a scarcely myelotoxic drug, L-asparaginase, was administered: a 10/13 (76.9%) remission of the disease was then achieved. This therapeutic trial was well accepted and could be more extensively used in the patients in relapse. A remission lasting between 4 and 28 weeks was observed.     

Hypergranular acute lymphoblastic leukemia (ALL)

Summary We report a case of adult acute lymphoblastic leukemia (ALL) with myeloid-like hypergranulation of blast cells. Like most of the granular ALLs described in the literature, the blast cells had L2 morphology and exhibited a common-ALL immunologic phenotype. The clinical findings at diagnosis were unremarkable. Cytogenetic analysis showed a 46XY karyotype. Molecular genetic analysis revealed T-cell receptor (TCR) and immunoglobulin heavy chain rearrangements; no rearrangement was found at the TCR gene locus. The polymerase chain reaction (PCR) for the BCR-ABL translocation was negative. The clinical course of the patient was uncomplicated. On standard ALL treatment protocol he achieved complete remission (CR) within 4 weeks, and he is currently disease free 8 months after diagnosis. The case contributes well-documented data to the characterization of adult granular ALL, with special regard to changes at the molecular genetic level.     

Efficacy of liposomal daunorubicin and cytarabine as reinduction chemotherapy in relapsed acute lymphoblastic leukaemia despite expression of multidrug resistance-related proteins

The treatment of relapsed adult acute lymphoblastic leukaemia (ALL) is frequently unsuccessful with current chemotherapy regimens, and often there is an overexpression of multidrug resistance (MDR)-related proteins. Liposomal encapsulation makes daunorubicin (DNR) less sensitive to the efflux effect of P-glycoprotein (PGP), and in vitro data indicate that liposomal-encapsulated DNR (Daunoxome-DNX) is more toxic than DNR against ALL cell lines. In this study, we assessed the in vivo and in vitro efficacy and toxicity of DNX plus cytarabine (Ara-C) as reinduction chemotherapy in 25 relapsed ALL patients (pts). The expression of MDR-related proteins (PGP, MRP1 and LRP) was also analysed. Of the 25 pts, 12 were males and 13 females; median age was 32 yr (range 18-58). Six cases were ALL T and 19 ALL B; eight pts were Ph+ (32%), and nine Bcr-Abl+ (36%). The expression of MDR-related proteins, and DNR and DNX retention and induction of apoptosis in leukaemic cells were evaluated in all cases. Seventeen of 25 (68%) pts were at first relapse and eight (32%) at second or subsequent relapse. The DNX was given in a dose of 80 mg/m(2)/d (days 1-3) in 11/25 pts (44%) and in a dose of 100 mg/m(2)/d (days 1-3) in 14/25 pts (66%). In all pts, Ara-C was administered in a dose of 2 g/m(2) (days 1-5). Twenty pts (80%) achieved a complete remission (CR) and two (8%) entered a partial remission (PR) for an overall response (OR) rate of 88% (22/25), with a tolerable toxicity and without significant cardiotoxicity. Before the start of DNX therapy, 18/25 (72%) cases overexpressed at least one MDR-related protein compared with 9/25 (36%) cases with MDR overexpression at diagnosis (P = 0.01). Taking into account the small number of cases, the response rate was not affected by MDR expression and the in vitro results also showed a higher uptake and apoptotic cell death by DNX compared with DNR. Twelve pts subsequently underwent allogeneic bone marrow transplantation (11 unrelated donor BMT, and one sibling BMT). The overall survival was 39% after 12 months. These data show the efficacy (OR rate 88% and CR rate 80%) of DNX plus Ara-C as reinduction therapy in very poor-risk ALL pts and the response rate seems not to be affected by MDR overexpression. Moreover, the high rate of remissions and the good clinical tolerance in heavily pretreated pts suggest a promising role of DNX in ALL chemotherapy regimens.     

High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia

High-dose methotrexate (MTX) has been extensively used for treatment of acute lymphoblastic leukemia (ALL). To determine the optimal dose of MTX in childhood relapsed ALL, the ALL Relapse Berlin-Frankfurt-Münster (ALL-REZ BFM) Study Group performed this prospective randomized study. A total of 269 children with a first early/late isolated (n = 156) or combined (n = 68) bone marrow or any isolated extramedullary relapse (n = 45) of precursor B-cell (PBC) ALL (excluding very early marrow relapse within 18 months after initial diagnosis) were registered at the ALL-REZ BFM90 trial and randomized to receive methotrexate infusions at either 1 g/m(2) over 36 hours (intermediate dose, ID) or 5 g/m(2) over 24 hours (high dose, HD) during 6 (or 4) intensive polychemotherapy courses. Intensive induction/consolidation therapy was followed by cranial irradiation, and by conventional-dose maintenance therapy. Fifty-five children received stem-cell transplants. At a median follow-up of 14.1 years, the 10-year event-free survival probability was .36 (+/- .04) for the ID group (n = 141), and .38 (+/- .04) for the HD group (n = 128, P = .919). The 2 groups did not differ in terms of prognostic factors and other therapeutic parameters. In conclusion, methotrexate infusions at 5 g/m(2) per 24 hours, compared with 1 g/m(2) per 36 hours, are not associated with increased disease control in relapsed childhood PBC acute lymphoblastic leukemia.     

High-dose cytarabine in upfront therapy for adult patients with acute lymphoblastic leukaemia

Summary. In this national study, we have evaluated a new intensive chemotherapy protocol for adult patients with untreated acute lymphoblastic leukaemia (ALL). One hundred and fifty-three patients with median age 42 years received induction therapy with high-dose cytarabine (Ara-C), cyclophosphamide, daunorubicin, vincristine and betamethasone. A high complete remission (CR) rate (90%) was achieved in patients < 60 years compared with 70% in patients > 60 years ( P  = 0·004). The estimated 3 year overall survival for all patients was 29% (CI 21–36%) and the estimated continuous complete remission (CCR) at 3 years for the patients achieving CR according to the protocol was 36% (CI 27–45%). A favourable pretreatment characteristic was pre-B phenotype, especially for patients < 40 years without any high-risk factor, with an estimated CCR at 3 years of 62% (CI 41–82%). Stem cell transplantation (SCT) as post-remission therapy, mainly for high-risk patients, gave an estimated 3 year disease free survival (DFS) after SCT of 39% (CI 24–54%). No significant differences in DFS could be found between autologous, related or unrelated donor transplantation. We conclude that this intensive protocol resulted in a high CR rate combined with acceptable side-effects and a favourable CCR for patients with pre-B ALL.     

High-dose cytosine arabinoside and daunorubicin as consolidation therapy for acute nonlymphocytic leukemia in first remission: a pilot study

High-dose (HD) cytosine arabinoside (ARA-C) is more effective treatment than conventional-dose ARA-C regimens for patients with relapsed acute nonlymphocytic leukemia (ANLL). We report here that HD ARA-C given during the first remission of ANLL has resulted in long remission durations and a high proportion of patients who survive more than three years free of disease. From August 1979 to September 1983, 36 adult patients with ANLL in first remission received one to three courses of HD ARA-C (3 g/m2 by one-hour infusion every 12 hours for 12 doses on days 1 through 6) alone or with daunorubicin (30 mg/m2 for two or three doses on days 7 through 9). Three patients died of sepsis or hemorrhage during consolidation, and 14 patients have relapsed from five to 48 months after diagnosis. The remaining 19 patients are in continued complete remission (CCR) from 11 to 62 months. Denoting all deaths in remission as relapse, the actuarial probability of CCR is 42% at 62 months, with an apparent plateau in the survival curve. Of the first 22 patients treated, ten remain in CCR from 37 to 62 months with no therapy for at least three years. Due to its heightened anti-leukemic activity, HD ARA-C allows brief but effective consolidation of ANLL in first remission, with long-term disease-free survival comparable to other approaches.     

改良VDLP方案治疗中老年急性淋巴细胞白血病的疗效

目的探讨改良VDLP方案治疗老年急性淋巴细胞白血病(ALL)的效果及不良反应。方法将2009年1月1日至2014年12月31日来该院就诊的初诊老年ALL患者随机分成实验组和对照组,对照组诱导化疗采取传统的VDLP方案(长春新碱2 mg,第1、8、15天;DNR 30~40 mg/m2,第1~3天,第15~16天;左旋门冬酰胺6 000~10 000 U,第11、14、17、20天;泼尼松1 mg/kg,第1~14天,继之减量,1~2 w减停);实验组诱导化疗采取改良VDLP方案诱导治疗(长春新碱2 mg,第1、8、15天;DNR 30 mg~40 mg/m2,第1~3天;左旋门冬酰胺酶6 000~10 000 U,第11、14、17、20天;泼尼松1 mg/kg,第1~14天,继之减量,1~2 w减停)。观察两组患者的缓解率及并发症。结果实验组与对照组CR率无统计学差异(P0.05),治疗相关死亡率、重症感染发生率有统计学差异(P0.05)。结论改良VDLP方案与传统VDLP方案相比有更好的耐受性,更适合老年ALL的诱导化疗。     

Sequentisl induction chemotherapy with vincristine,daunorubicin cyclophosphamide,and prednisone in adult acute lymphoblastic leukemia

Sequential chemotherapy with vincristine, daunorubicin, cyclophosphamide, and prednisone doses was administered to 57 adult patients with acute lymphoblastic leukemia (ALL). Complete remission (CR) was achieved in 51 (89%, 95% confidence intervals, [CI] 78–96%). Among patients achieving CR, 62% were in CR after one sequence of chemotherapy, 23% after two sequences, and 5% after three sequences. Six patients (11%) had resistant disease. All patients experienced profound myelosuppression. Median time to recovery of neutrophils > 0.5 × 10⁹/l was 22 days (range: 5–89 days), and of platelets >100×l0⁹/l 21 days (range: 0–45 days). Nonhematologic WHO grade 3 or more side effects consisted predominantly of hyperbilirubinemia (7%), mucositis (5%), nausea and vomiting (2%), and cutaneous toxicity (1%). Severe infectious complications occurred in only 14% of cases. One patient (2%, 95% CI 0–9%) died of therapy-related toxicity while in early CR. We concluded that sequential use of prednisone seemed at least as effective as continuous administration at the expense of a few adverse side effects.