Combination chemotherapy with low-dose cytarabine, homoharringtonine, and granulocyte colony-stimulating factor priming in patients with relapsed or refractory acute myeloid leukemia

As sensitization of leukemic cells with granulocyte colony-stimulating factor (G-csf) can enhance the cytotoxicity of chemotherapy in acute myeloid leukemia (AML), a pilot study was conducted in order to evaluate the effect of G-csf priming combined with low-dose chemotherapy in patients with relapsed and refractory AML. The regimen, G-HA, consisted of cytarabine 7.5 mg/m2/12 hr by subcutaneous injection, days 1-14, homoharringtonine 1.5 mg/m2/day by intravenous continuous infusion, days 1-14, and G-csf 150 microg/m2/day by subcutaneous injection, days 0-14. Thirty-six AML patients were enrolled, 23 refractory and 13 relapsed. Eighteen patients (50%, 95% confidence interval: 33-67%) achieved complete remission (CR) with a median CR duration of 7.2 months, and two elderly patients continued a regimen of maintenance therapy and remained in remission for 26.3 and 14.1 months, respectively, as of last follow-up. Eight patients (22%) experienced neutropenia (median duration: 6 days; range: 2-22 days). Thirteen of the 36 (36%) developed severe infections. Grade 1-2 nonhematologic toxicities were documented, including nausea and vomiting (20%), liver function abnormality (6%), and heart function abnormality (6%). No central nervous system and kidney toxicity was observed. The G-HA regimen is effective in remission induction for refractory and relapsed AML patients and well tolerated in maintenance therapy in some subgroups of elderly patients. Further studies are necessary to elucidate optimum dose and schedule for this regimen to enhance the treatment efficacy of relapsed or refractory AML patients.     

Fludarabine and cytarabine in patients with relapsed acute myeloid leukemia refractory to initial salvage therapy

The most effective regimen for relapsed acute myeloid leukemia (AML) patients who do not achieve complete remission (CR) after a course of salvage therapy has not been established. We evaluated the efficacy and toxicity of fludarabine and cytarabine in patients with AML in first relapse who did not respond to a course of salvage chemotherapy with mitoxantrone and etoposide. CR was achieved in 39 % of treated patients, and in 47 % of patients with a favorable/intermediate-risk karyotype. The median overall survival was 4.75 months. The median survival for patients achieving CR with fludarabine–cytarabine was significantly higher than for those who did not respond to therapy (9.6 vs. 4.5 months, P = 0.04). Our data suggest that the fludarabine–cytarabine regimen merits further investigation in relapsed AML patients with favorable or intermediate-risk karyotype with persistent leukemia after a course of salvage therapy.     

Idarubicin, cytarabine, and topotecan in patients with refractory or relapsed acute myelogenous leukemia and high-risk myelodysplastic syndrome.

In an effort to develop more effective therapy for patients with refractory or relapsed acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS), we investigated the efficacy of a combination chemotherapy consisting of idarubicin, cytarabine, and topotecan. Twenty-seven patients were treated: four with primary refractory AML, nine with AML in first relapse, four with AML in second relapse, and 10 with MDS-RAEB/RAEBT. Patients received as salvage therapy a single course of idarubicin 12 mg/m(2) IV bolus on days 1-3, cytarabine 1 g/m(2) over two hours q 12 hr on days 1-5, and topotecan 1.25 mg/m(2) over 24 hr on days 1-5. Median age was 42 years (range 17-65 years). All patients were evaluable for response: 14 (51.9%) achieved complete remission, 10 with AML (59%) and four with MDS (40%), respectively. Thirteen AML patients (excluding four relapsed after autologous stem cell transplantation) were grouped into four categories to stratify the probability of achieving complete remission (CR): group 1, first CR duration > or = 2 years and receiving first salvage treatment (S1); group 2, first CR duration 1-2 years and receiving S1; group 3, first CR duration 0-1 years and receiving S1; and group 4, first CR duration 0-1 years and receiving S2, S3, or S4 after failing S1. The response rate of each group was as follows: group 1, one of two (50%); group 2, one of one (100%); group 3, four of four (100%); group 4, two of six (33.3%). The median remission duration and survival of patients with AML were six and 12 months, respectively. Median duration of survival in 10 MDS patients was 15 months, and all four MDS patients achieving a CR maintained continuous CR with a median follow-up of 11 months. Severe myelosuppression was observed in all patients, resulting in fever or documented infections in 89% of patients. Median time to recovery of neutrophils > or =0.5 x 10(9)/l was 22 days (11-34) and for platelets > 20 x 10(9)/l 35 days (11-58). Reversible grade 3-4 toxicities included diarrhea (two patients) and mucositis (seven patients). We conclude that combination chemotherapy with intermediate dose cytarabine, idarubicin, and topotecan has significant antileukemic activity and acceptable toxicity in salvage AML and high-risk MDS.     

Improvement of prognosis in refractory and relapsed acute promyelocytic leukemia over recent years: the role of all-trans retinoic acid therapy

 With the aim of determining the ability of all-trans retinoic acid (ATRA) to improve prognosis in refractory and relapsed acute promyelocytic leukemia (APL), the data of 45 patients resistant to previous conventional chemotherapy or in first relapse were retrospectively reviewed. Thirty-seven patients presented with typical M3, five with variant form (M3v), and three with intermediate form. Seven patients died before any chemotherapy could be given. Thirty-five patients received one course of chemotherapy combining anthracyclines and cytarabine without (n=22) or with ATRA (n=13), according to different protocols. One elderly patient received only ATRA, and two patients received only low-dose cytarabine. Nine patients died within 4 weeks of relapse. A complete remission (CR) was achieved in 29 of the 38 patients retreated after first relapse or primary failure (76.3%, 95% CI: 60–89%). Among relapsed patients, four of five patients who had initially received ATRA therapy achieved a second CR when retreated by ATRA. The median second disease-free survival (DFS) was 23.3 months. Overall median survival was 7.8 months, with a 5-year survival rate of 29% (95% CI: 14–44%). Parameters found to be associated with decreased second CR rate were presence of hemorrhages and hemostatic disorder, and high levels of GGT at the time of relapse. Factors associated with short survival were WHO performance status >1, high serum LDH levels, and coagulopathy at time of relapse. Use of ATRA at time of relapse (n=14) was significantly associated with higher CR rates (p=0.008), longer DFS (median not reached versus 7.9 months;p=0.05), and longer survival after first relapse (median 32.3 months versus 4.4 months;p=0.003). In the multivariate analysis, the only factor predictive of poor prognosis for overall survival was the absence of ATRA therapy at relapse. We conclude that ATRA is effective in the treatment of relapsed or refractory APL and appears superior to chemotherapy alone. Received: 13 June 1997 / Accepted: 8 September 1997     

A multicenter,open, non-comparative,phase II study of the combination of cladribine (2-chlorodeoxyadenosine), cytarabine,and G-CSF as induction therapy in refractory acute myeloid leukemia - a report of the Polish Adult Leukemia Group (PALG)

OBJECTIVES: To evaluate the efficacy and toxicity of cladribine (2-chlorodeoxyadenosine, 2-CdA), cytarabine (Ara-C), and granulocyte-colony stimulating factor (G-CSF) (CLAG) regimen in refractory acute myeloid leukemia (AML) in the multicenter phase II study. METHODS: The induction chemotherapy consisted of 2-CdA 5 mg/m2, Ara-C2 g/m2, and G-CSF. In the case of partial remission (PR), a second CLAG was administered. Patients in complete remission (CR) received two consolidation courses based on HD Ara-C, mitoxantrone or idarubicine, with or without 2-CdA. RESULTS: Fifty-eight patients from 11 centers were registered; 50 primary resistant and eight early relapsed (CR1 < 6 months). CR was achieved in 29 (50%) patients, 19 (33%) were refractory, and 10 (17%) died early. Forty of 50 primary resistant patients received daunorubicin (DNR) and Ara-C as the first-line induction therapy (DA-7), 10 received additional 2-CdA (DAC-7). The CR rates after CLAG were 58% and 10%, respectively in each group (P = 0.015). Five of six patients with myelodysplastic syndrome (MDS)/AML achieved CR. Hematologic toxicity was the most prominent toxicity of this regimen. The overall survival (OS, 1 yr) for the 58 patients as a whole, and the 29 patients in CR were 42% and 65%, respectively. Disease-free survival (DFS, 1 yr) was 29%. Only first-line induction treatment with DA-7 significantly influenced the probability of CR after CLAG. None of the analyzed factors significantly influenced DFS and OS. CONCLUSION: CLAG regimen has significant anti-leukemic activity and an acceptable toxicity in refractory AML. The addition of 2-CdA to the first-line induction treatment may worsen the results of salvage with CLAG. The high CR rate in patients with MDS preceding AML deserves further observation.     

Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia

Nineteen patients with high-risk myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) received fludarabine, cytarabine, granulocyte-colony stimulating factor (G-CSF), and idarubicin chemotherapy ( de novo MDS/MDS-AML, nine; relapsed/refractory MDS/AML, seven; therapy-related MDS, three). Median age was 44 years and median disease duration 10 months. 16/19 (84%) patients had abnormal cytogenetics with seven (37%) harbouring abnormalities of chromosome 7. 18/19 (94.7%) patients responded to FLAG-idarubicin with 12 (63%) achieving complete remission (CR) (<5% blasts and normal cytogenetics). 7/9 (78%) patients with de novo MDS/MDS-AML achieved CR compared to 5/10 (50%) with alternative diagnoses. Response was associated with age < 50 years, disease duration < 3 months, and cytogenetics other than abnormalities of chromosome 7. Haemopoietic regeneration was rapid in most patients and there were no toxic deaths. Nine patients received a second course of chemotherapy, three have proceeded to allogeneic bone marrow transplant and three to autologous blood stem cell/bone marrow transplantation. Follow-up is short (median 10 months). 12/19 (63%) patients remain alive and 5/12 (42%) have relapsed at a median 5 months following CR achievement. FLAG-idarubicin was well tolerated. High rates of morphological and cytogenetic remission, especially in de novo MDS, offer a window of opportunity for assessment of autologous BMT in this group of diseases where no treatment except alloBMT has led to prolongation of survival.     

Continuous intravenous administration of daunorubicin and cytarabine for remission induction of poor risk acute myelogenous leukaemias and myelodysplastic syndromes

Seventeen consecutively admitted poor risk acute myeloid leukaemia (AML) patients and 4 patients with myelodysplastic syndrome (MDS) were treated with a remission-induction regimen consisting of a 7-day continuous intravenous infusion of conventional doses of cytarabine and of three 24-h constant rate infusions of daunorubicin administered intermittently on days 1, 3 and 5. The diagnoses were: relapsed primary AML in 6 patients, secondary AML in 11 patients (9 untreated, 2 relapsed) and MDS in 4 patients. The median age was 50 yr. Five of 6 patients with relapsed primary AML, 3 of 11 patients with secondary AML and 2 of 4 patients with MDS achieved complete remission (CR). The overall CR rate was 48% with a median remission duration of 5 months (range: 0.25-20 months). Few acute toxic side effects were observed thanks to the constant rate of infusion of daunorubicin.     

Phase II study of mitoxantrone and cytarabine in acute myeloid leukemia

Thirty-eight patients with acute myeloid leukemia (AML) were treated with mitoxantrone (Mto) combined with cytarabine (Ara-C). Five patients had received no previous treatment for acute myeloid leukemia, seven were refractory to treatment with standard first-line chemotherapy, eight had relapsed during treatment, and 18 had relapsed after treatment was stopped. Eleven of these relapses were early (within 6 months of stopping treatment). Mto was given for 5 days by iv bolus injection at a dose of 10 mg/m2 to 12 patients and at 12 mg/m2 to 26. Ara-C was given at a dose of 1 g/m2 twice daily by a 2-hour infusion for 3 days to 37 patients. One patient received Ara-C at a dose of 500 mg/m2 twice daily for 3 days. Toxicity was acceptable except for cerebellar toxicity in two patients, which was irreversible in one. Twenty-two patients (56%) achieved complete remission (CR), and four achieved partial remission (10%). Seventy-five percent of the patients who had relapsed during treatment and 58% of those who had relapsed after treatment was stopped achieved CR. Eleven patients remain in CR at a median time of 10 months (range, 3-17) after treatment. In five patients remissions have lasted greater than 1 year, one in a patient treated in second relapse and one in a patient treated in third relapse. Mto and Ara-C appear to be effective salvage therapy in acute myeloid leukemia and should be considered for incorporation into first-line induction regimens.     

Etoposide in combination with cytarabine, doxorubicin, and 6-thioguanine for treatment of acute nonlymphoblastic leukemia in a protocol adjusted for age

Etoposide combined with cytarabine, doxorubicin, and 6-thioguanine was used to treat 34 patients with acute nonlymphoblastic leukemia (ANLL) in an age-adjusted protocol, with patients greater than 50 years old receiving fewer days of therapy. Complete remissions (CR) occurred in 85% of all patients (29 of 34 patients). Patients less than or equal to 50 years of age achieved a 94% CR rate (17 of 18 patients) compared to a 75% CR rate (12 of 16 patients) in older patients. Duration of remission was less for those greater than 50 years of age. The remission rate for primary ANLL was 86% (19 of 22 patients) and for secondary or relapsed ANLL was 83% (ten of 12 patients). Thus, this is effective therapy for primary and secondary or relapsed ANLL. When the days of therapy are reduced for older patients' age, the remissions are fewer and less durable.     

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.     

Mitoxantrone and etoposide: an effective regimen for refractory or relapsed acute myelogenous leukemia

23 adult patients with refractory or relapsed acute myelogenous leukemia (AML) received salvage chemotherapy with mitoxantrone and etoposide. The regimen consisted of mitoxantrone, 10 mg/m2/d by 30-min infusion, and etoposide 100 mg/m2/d by 30-min infusion, given 12 h apart for 5 consecutive d. Of 23 patients treated, 13 met the criteria for highly refractory disease (6 primary resistant; 4 with early relapse during maintenance; 3 relapsed and refractory to reinduction). 10 patients had relapsed off-therapy more than 6 months after achieving first CR. Overall, 14 patients (61%) achieved a complete remission (CR): 6/13 (46%) with refractory AML, and 8/10 (80%) with relapsed AML. 2 patients had a partial remission, 2 died in aplasia, and 5 were nonresponders. In responding patients, the median time for recovery of granulocyte count was 27 d. The most important nonhematologic side effect was oral mucositis, which was severe in 35% of cases. No signs of cardiac toxicity were observed. The median CR duration was 5 months (range, 2 to 12+ months). The combination of mitoxantrone and etoposide appears a highly effective and relatively well tolerated salvage regimen for refractory and relapsed AML. Its incorporation into first-line induction and consolidation programs for newly diagnosed AML patients should be considered.     

Treatment of relapsed acute lymphoblastic leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a prospective study

Donor leukocyte infusion (DLI) alone has very limited efficacy for patients with acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic bone marrow transplantation (BMT). We, therefore, prospectively tested the efficacy of cytoreductive chemotherapy (intermediate-dose cytarabine+idarubicin+etoposide) followed immediately by G-CSF-primed DLI (Chemo-DLI) in 10 relapsed ALL patients after allogeneic BMT. Seven achieved complete remission (CR) at a median of 25 days (19-73 days) after DLI. Of these seven CR patients, only one remains alive in CR 907 days after DLI. Two CR patients died in CR of graft-versus-host disease. The remaining four CR patients relapsed at a median of 153 days (120-991 days) after DLI. One is alive with leukemia at post-DLI day 1217. The median survival duration after DLI was 175 days (15-1217 days). In summary, although Chemo-DLI for relapsed ALL after allogeneic BMT induced a relatively high CR rate, durable remissions were rare. Although our data should be interpreted cautiously considering the small number of patients, these results suggest that poor outcome of DLI in relapsed ALL may be primarily due to intrinsic resistance to graft-versus-leukemia effect rather than to the rapid pace of the disease.     

Fludarabine,cytarabine, and G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia

Thirty-eight patients with primary resistant or relapsing acute myeloid leukemia (AML) were treated with fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG). Median age was 41 (range 11–70). Sixteen patients had AML that was primary resistant to induction treatment, while 22 were relapsed, 11 after autologous bone marrow transplant (AuBMT), 8 less than 6 months from complete remission (CR) achievement, and 3 were second relapse from chemotherapy alone. Overall, 21 of 38 patients (55%) obtained CR. Age, sex, length of CR, and interval between autoBMT and FLAG administration did not significantly influence the CR rate. On the contrary, a normal karyotype at diagnosis was significantly related to a better outcome. There were 4 induction deaths (10%), due to fungal infection in 2 patients and hemorrhagic complications in the remaining two. All patients experienced profound cytopenia. Median time to neutrophil (>500/μl) recovery was 21 days, while a platelet count >20,000/μl was reached after 23 days. The median period of hospitalization was 31 days. The nonhematological toxicity was mild, mainly consisting of mucositis. There were 17 documented infections and 17 episodes of fever of unknown origin. Following CR achievement, 6 patients received autoBMT, 3 alloBMT, 2 high-dose arabinosil-cytosine, and 2 are on a waiting list for transplantation procedure. We conclude that FLAG is an effective and well-tolerated regimen for refractory or recurrent AML, mainly useful for patients to be admitted to bone marrow transplantation. Am. J. Hematol. 58:105–109, 1998. © 1998 Wiley-Liss, Inc.     

Factor XI deficiency in Iranians: its clinical manifestations in comparison with those of classic hemophilia

BACKGROUND AND OBJECTIVES: Patients affected by Hodgkin's disease (HD) resistant to induction therapy or who have a brief duration of first remission have a poor outcome. DESIGN AND METHODS: We retrospectively reviewed the clinical data of 28 patients affected by Hodgkin's disease who relapsed 6 to 24 months from completion of treatment (14 patients) or who were refractory to first-line therapy or relapsed very early (14 patients). All the 28 patients were treated with salvage chemotherapy plus a conditioning regimen followed by peripheral blood stem cell transplant (PBCST) or autologous bone marrow transplant (ABMT). RESULTS: At a median follow-up of 35.5 months (range 14-119), of the 14 patients responding to first-line therapy but who relapsed > 6 months off therapy, 10 (72%) are alive, well and in complete remission (CR), 2 (14%) are alive with disease at 39 and 83 months from transplant, and 2 (14%) died 26 and 63 months after their transplant from acute myeloid leukemia and HD, respectively. At a median follow-up of 39 months, the overall survival (OS) is 68% and the event-free survival (EFS) is 56%. At a median follow-up of 30 months (1-98), of the 14 patients refractory to first-line therapy or who relapsed very early, 9 (64%) are alive in CR, 1 (7%) is alive with disease and 4 (29%) have died of their disease (3 patients) or myelodysplastic syndrome (1 patient). The OS is 58% and the EFS is 52%. There are no statistically significant differences in terms of OS and EFS between the two groups of patients. INTERPRETATION AND CONCLUSIONS: Our study shows that salvage chemotherapy followed by a conditioning regimen and autotransplant is an effective, feasible and well-tolerated scheme of therapy not only for patients with HD who relapse after first-line treatment, but also for those resistant to first-line treatment.     

Time sequential chemotherapy for primary refractory or relapsed adult acute myeloid leukemia: results of the phase II Gemia protocol

BACKGROUND AND OBJECTIVE: High-dose cytarabine (HDAra-C), mitoxantrone and etoposide are the mainstay of several active regimens against relapsed or refractory acute myelogenous leukemia (AML). We designed a phase II study to assess the efficacy and side effects of a time sequential application of mitoxantrone plus intermediate-dose Ara-C followed by HDAra-C plus etoposide (GEMIA) in adult patients with refractory or relapsed AML. DESIGN AND METHODS: Patients with refractory or relapsed AML were eligible for GEMIA salvage therapy, which comprised mitoxantrone 12 mg/m2/day on days 1-3, Ara-C 500 mg/m2/day as a 24-hour continuous infusion on days 1-3, followed by HDAra-C 2 g/m2/12-hourly on days 6-8 and etoposide 100 mg/m2/12-hourly on days 6-8. Granulocyte colony-stimulating factor was started on day 14. In patients above the age of 55 the dose of Ara-C in the first sequence (days 1-3) was reduced to 250 mg/m2. RESULTS: Twenty patients were included, of whom 12 achieved complete remission after GEMIA (60%, 95% CI 40-80%), one was refractory and five died early from infection. Two additional patients achieved partial remission after GEMIA and complete remission after consolidation chemotherapy, for a final CR rate of 70% (95% CI 48-88%). Neutrophils recovered at a median of 27 days (range, 22-43) and platelets 46 days (range, 25-59) after the start of treatment. The median duration of remission was 133 days (range, 36-417+) whereas overall survival time lasted for a median of 153 days (range, 13-554+). Treatment-associated toxicity was comprised predominantly of infection, mucositis and diarrhea that reached World Health Organization grades III-V in 40%, 40% and 30% of patients, respectively. Despite the intention to rapidly proceed to a hematopoietic stem cell transplant in patients in remission, only five patients reached the transplant. INTERPRETATION AND CONCLUSIONS: The GEMIA time sequential chemotherapy regimen appears effective in obtaining remissions in refractory and relapsed adult AML. The high toxicity seen, however, suggests that its design is amenable to further improvements, especially in more elderly patients. Since remissions are short-lived, more innovative post-remission strategies are needed.     

Dose intensification with autologous stem cell transplantation in relapsed and resistant Hodgkin's disease

BACKGROUND AND OBJECTIVES: Patients affected by Hodgkin's disease (HD) resistant to induction therapy or who have a brief duration of first remission have a poor outcome. DESIGN AND METHODS: We retrospectively reviewed the clinical data of 28 patients affected by Hodgkin's disease who relapsed 6 to 24 months from completion of treatment (14 patients) or who were refractory to first-line therapy or relapsed very early (14 patients). All the 28 patients were treated with salvage chemotherapy plus a conditioning regimen followed by peripheral blood stem cell transplant (PBCST) or autologous bone marrow transplant (ABMT). RESULTS: At a median follow-up of 35.5 months (range 14-119), of the 14 patients responding to first-line therapy but who relapsed > 6 months off therapy, 10 (72%) are alive, well and in complete remission (CR), 2 (14%) are alive with disease at 39 and 83 months from transplant, and 2 (14%) died 26 and 63 months after their transplant from acute myeloid leukemia and HD, respectively. At a median follow-up of 39 months, the overall survival (OS) is 68% and the event-free survival (EFS) is 56%. At a median follow-up of 30 months (1-98), of the 14 patients refractory to first-line therapy or who relapsed very early, 9 (64%) are alive in CR, 1 (7%) is alive with disease and 4 (29%) have died of their disease (3 patients) or myelodysplastic syndrome (1 patient). The OS is 58% and the EFS is 52%. There are no statistically significant differences in terms of OS and EFS between the two groups of patients. INTERPRETATION AND CONCLUSIONS: Our study shows that salvage chemotherapy followed by a conditioning regimen and autotransplant is an effective, feasible and well-tolerated scheme of therapy not only for patients with HD who relapse after first-line treatment, but also for those resistant to first-line treatment.     

Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: a bridge to transplantation

BACKGROUND AND OBJECTIVES: Arsenic trioxide (ATO) has been reported to be a safe and effective treatment for relapsed acute promyelocytic leukemia (APL). The aim of this study was to evaluate the efficacy and toxicity as well as the eligibility to stem cell transplantation (SCT) in a series of 7 patients with relapsing APL, managed with ATO. DESIGN AND METHODS: Seven patients with relapsing APL while on maintenance treatment with all-trans-retinoic acid (ATRA) or who were ATRA refractory-received ATO at a dose of 10 mg daily by 2-hour intravenous infusion until complete remission (CR). After consolidation chemotherapy, patients were programmed to receive autologous or allogeneic stem cell transplantation (SCT) according to donor availability. The median age of the patients was 55 (21-71) years: 2 patients presented with concomitant extramedullary relapse. RESULTS: Six patients (86%) achieved CR after a median of 35 ATO doses (20-49) with negligible toxicity; one patient died from pneumonia. After consolidation with a four-day course of cytarabine at 1 g/m2 and mitoxantrone 6 mg/m2, two patients underwent allogeneic SCT, two received PML/RARa negative autologous peripheral blood stem cells collected after consolidation plus granulocyte colony-stimulating factor, one failed mobilization and received a second consolidation course. One elderly patient refused further treatment and relapsed 6 months later. After a median follow-up of 15 months from CR2 achievement, 5 patients are alive in continuous CR. INTERPRETATION AND CONCLUSIONS: The high CR rate and the mild toxicity confirm that ATO represents a valid alternative to salvage chemotherapy for patients relapsing while on ATRA treatment or who are ATRA-refractory. Allogeneic or autologous SCT after ATO-induced CR is feasible in the majority of patients.     

A phase I study of lenalidomide plus chemotherapy with mitoxantrone,etoposide, and cytarabine for the reinduction of patients with acute myeloid leukemia

Patients with relapsed AML have a poor prognosis and limited responses to standard chemotherapy. Lenalidomide is an immunomodulatory drug that may modulate anti‐tumor immunity. We performed a study to evaluate the safety and tolerability of lenalidomide with mitoxantrone, etoposide and cytarabine (MEC) in relapsed/refractory AML. Adult patients with relapsed/refractory AML were eligible for this phase I dose‐escalation study. We enrolled 35 patients using a “3 + 3” design, with a 10 patient expansion cohort at the maximum tolerated dose (MTD). Lenalidomide was initially given days 1‐14 and MEC days 4‐8; due to delayed count recovery, the protocol was amended to administer lenalidomide days 1‐10. The dose of lenalidomide was then escalated starting at 5 mg/d (5‐10‐25‐50). The primary objective was tolerability and MTD determination, with secondary outcomes including overall survival (OS). The MTD of lenalidomide combined with MEC was 50 mg/d days 1‐10. Among the 35 enrolled patients, 12 achieved complete remission (CR) (34%, 90%CI 21‐50%); 30‐day mortality was 6% and 60‐day mortality 13%. The median OS for all patients was 11.5 months. Among 17 patients treated at the MTD, 7 attained CR (41%); the median OS was not reached while 12‐month OS was 61%. Following therapy with MEC and lenalidomide, patient CD4+ and CD8+ T‐cells demonstrated increased inflammatory responses to autologous tumor lysate. The combination of MEC and lenalidomide is tolerable with an RP2D of lenalidomide 50 mg/d days 1‐10, yielding encouraging response rates. Further studies are planned to explore the potential immunomodulatory effect of lenalidomide and MEC.     

Autologous bone marrow transplantation in patients with AML in first complete remission. Results of two different conditioning regimens after the same induction and consolidation therapy

Thirty-nine patients with acute myeloblastic leukemia (AML) in first complete remission (CR) were treated by autologous bone marrow transplantation. All patients received the same induction and consolidation chemotherapy consisting of a combination of daunorubicin (DNR) and cytarabine (Ara-C) followed by four courses of DNR, Ara-C and 6-thioguanine (6-TG). Two different conditioning regimens were used; 25 patients were submitted to the BAVC regimen (BCNU, amsacrine, VP-16 (etoposide) and Ara-C) and 14 to a cyclophosphamide/total body irradiation (CY + TBI) regimen. Six patients (one treated with BAVC and five treated with CY + TBI) died in aplasia. Twelve of the 25 BAVC treated patients and one of the nine CY + TBI treated patients relapsed; 12 (48%) of the BAVC treated patients are in CR with a median follow-up of 45 months and eight (57%) of the CY + TBI treated patients are in CR with a median follow-up of 50 months. All patients in CR have survived for more than 2 years since transplant.     

Salvage treatment for primary resistant acute myelogenous leukemia consisting of intermediate-dose cytosine arabinoside and interspaced continuous infusions of idarubicin: A phase-II study (no. 06901) of the EORTC Leukemia Cooperative Group

 Twenty-one patients with acute myeloid leukemia (AML) who failed to enter complete remission (CR) after first-line standard-dose remission-induction therapy with 7 days of cytarabine and 3 days of daunorubicin were treated with a salvage regimen containing intermediate-dose cytosine arabinoside (Ara-C) 2×500 mg/m²/day during 7 days in combination with continuous infusions of idarubicin 12 mg/m²/day on days 1, 3, and 5. Twenty patients were considered primary resistant, and one patient had a partial remission after two remission-induction courses. Overall, 11 patients (52%, 95% confidence interval: 30–74%) entered CR. Three patients died during hypoplasia and seven patients had resistant disease or a partial remission. The remission rate in this study compares favorably with the results obtained in similar patient categories. The toxicity of this salvage regimen was remarkably mild. No extramedullary toxicity was observed except for hepatic dysfunction in seven patients. The median duration of remission was 8.5 months, and ultimately, all complete remitters have relapsed except the patient who died from infectious complications after allogeneic bone marrow transplantation (BMT). This study shows that new intensive chemotherapy regimens may be effective after failure of primary treatment. Salvage regimens containing intermediate/high-dose Ara-C and/or alternative anthracyclines or anthracenes should be induced in the treatment of young patients with de novo AML. Received: 12 September 1995 / Accepted: 24 November 1995