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.     

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.     

Efficacy of fractionated gemtuzumab ozogamicin combined with cytarabine in advanced childhood myeloid leukaemia

Gemtuzumab ozogamicin (GO) monotherapy is reported to yield a 20-30% response rate in advanced acute myeloid leukaemia (AML). This study examined the efficacy and tolerability of GO combined with cytarabine (GOCYT) in children with refractory/relapsed CD33(+) AML. Seventeen children received GO 3 mg/m(2) on days 1, 4 and 7 plus cytarabine 100 mg/m(2)/d for 7 d on a compassionate-use basis. Seven patients then received GO-based consolidation. At the outset of GOCYT, two patients were refractory; eight patients were in refractory first relapse; six patients had relapsed after stem cell transplantation (SCT); and one patient [del(5q) therapy-related AML (t-AML)] had not yet been treated. Mean follow-up was 17 months (8-33 months). Ten responses were obtained after GOCYT induction, including complete remission (CR) or CR without complete recovery of platelets (CRp) in six patients (35%). The responses improved in three children who received GOCYT consolidation, increasing the CR + CRp rate to 53%. SCT was subsequently performed in eight responders. Grade 3-4 adverse events consisted of haematological disorders (n = 17, 100%) and documented infections (n = 5, 29%). No cases of sinusoidal obstructive syndrome occurred. Three patients were alive at the cut-off date for this analysis, all of whom had responded to GOCYT. GOCYT combination therapy yielded a high response rate (53%) and showed acceptable toxicity in heavily pretreated children with refractory/relapsed AML. These results warrant a larger prospective study.     

Intermediate and high-dose ARA-C and m-AMSA (or daunorubicin) as remission and consolidation treatment for patients with relapsed acute leukaemia and lymphoblastic non-Hodgkin lymphoma

27 patients (aged 15-55 years) with relapsed acute myelogenous (AML) and lymphoblastic leukaemia (ALL), and with lymphoblastic non Hodgkin's lymphoma (NHL) have been treated with intermediate dose cytosine arabinoside (AraC, 1 g/m2 q 12 h X 12) and 3 d of m-AMSA (20 patients), 90-115 mg/m2 daily, or daunorubicin (7 patients). 18 of them attained a complete remission (AML 10/14, ALL 3/5, NHL 5/8). 7 patients received consolidation treatment with 1-2 courses comprising 4 d of AraC (3 g/m2 q 12 h X 8) and m-AMSA (90-115 mg/m2) on d 5 of each course. 2 patients underwent allogeneic bone marrow transplantation and 9 received no further treatment after remission induction. In addition to vomiting, fever and conjunctivitis, toxicity in 6 patients included a combination of severe diarrhoea, fever and signs of paralytic ileus. 3 of them died during the pancytopenic phase. The pancytopenic period ranged from 16-25 d (median 21 d) after the remission induction and 14-21 d (median 19 d) after the consolidation course. Median remission duration was 5 months for those patients who received no treatment after remission induction and greater than 9 months (4+ - 16+ months) for the patients who received consolidation courses. Increased dosages of AraC are active in relapsed leukaemia and lymphoma, although optimal dose and schedule are still undetermined.     

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.     

Increasing the dose of aclarubicin in low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (CAG regimen) can safely and effectively treat relapsed or refractory acute myeloid leukemia

It is difficult for relapsed and refractory acute myeloid leukemia (AML) patients to achieve complete remission (CR). The CAG regimen [low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (G-CSF)] has been used to treat relapsed and refractory AML patients, and showed good therapeutic efficacy. It is unknown, however, whether increasing the dose of aclarubicin in CAG regimen could treat relapsed or refractory AML safely and effectively. We evaluate the efficacy and tolerability of increasing the dose of aclarubicin in CAG regimen, in 37 relapsed or refractory AML patients. All patients were treated with CAG regimen including low-dose cytarabine (10 mg/m² every 12 h, days 1–14), aclarubicin (5–7 mg/m² every day, days 1–14), and G-CSF (200 μg/m² every day, days 1–14) priming. After a single course of therapy, the overall response [CR + partial remission (PR)] rate of all patients was 78.4 % (29/37), in which the CR rate was 62.2 % (23/37). There was no early death. The median overall survival was 6 months (range 2–36 months). Myelosuppression was ubiquitous, but tolerated. No severe non-hematologic toxicity was observed. Thus, increasing the dose of aclarubicin in CAG regimen can be used safely and effectively in the treatment of relapsed or refractory AML.     

Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with advanced CD33+ acute myeloid leukemia

This open-label, dose-escalation study evaluated the safety and efficacy of single-agent gemtuzumab ozogamicin, a humanized anti-CD33 antibody-targeted chemotherapeutic agent, for pediatric patients with multiple relapsed or primary refractory acute myeloid leukemia (AML). Twenty-nine children 1 to 16 years of age (relapsed disease, 19; refractory disease, 10) received gemtuzumab ozogamicin ranging from 6 to 9 mg/m2 per dose for 2 doses (separated by 2 weeks) infused over 2 hours. All patients had anticipated myelosuppression. Other toxicities included grade 3/4 hyperbilirubinemia (7%) and elevated hepatic transaminase levels (21%); the incidence of grade 3/4 mucositis (3%) or sepsis (24%) was relatively low. One patient treated at 9 mg/m2 developed veno-occlusive disease (VOD) of the liver and defined the dose-limiting toxicity. Thirteen patients underwent hematopoietic stem-cell transplantation less than 3.5 months after the last dose of gemtuzumab ozogamicin; 6 (40%) developed VOD. Eight of 29 (28%) patients achieved overall remission. Remissions were comparable in patients with refractory (30%) and relapsed (26%) disease. Mean multidrug resistance-protein-mediated drug efflux was significantly lower in the leukemic blasts of patients achieving remission (P < .005). Gemtuzumab ozogamicin was relatively well tolerated at 6 mg/m2 for 2 doses and was equally effective in patients with refractory and relapsed disease. Further studies in combination with standard induction therapy for childhood AML are warranted.     

Treatment of relapsed and refractory acute myeloid leukemia with diaziquone and mitoxantrone: a CALGB phase I study

Twenty-one patients with relapsed or refractory acute myeloid leukemia (AML) were treated with mitoxantrone (12 mg/m2/day, days 1-3) and diaziquone (continuous infusion days 1-5). The dosage of diaziquone was increased for sequential cohorts of seven patients from 20 mg/m2/day to 24 mg/m2/day, and finally to 28 mg/m2/day to determine the maximum tolerated dose for this chemotherapy combination. Myelosuppression was the dose-limiting toxicity. The median time to recovery of blood counts was greater at the highest dose of diaziquone (48 days) than at the lower two doses (31 and 28 days). Other toxic effects were minimal. Overall, 9/21 (43%, 95% confidence interval, 0.22 to 0.66) patients achieved complete remission. We conclude that this combination of drugs shows sufficient antileukemic activity with acceptable toxicity to warrant further trials.     

Cytarabine and clofarabine after high‐dose cytarabine in relapsed or refractory AML patients

Clofarabine has been shown to be effective in AML patients, either as single agent or, mainly, in association with intermediate dose cytarabine. Based on these reports, we conducted a preliminary study combining clofarabine and intermediate dose cytarabine in AML patients who relapsed or failed to respond to at least two induction therapies. We treated 47 patients affected by relapsed/refractory AML with a regimen including clofarabine at 22.5 mg/m² daily on days 1–5, followed after 3 hr by cytarabine at 1 g/m² daily on days 1–5. Ten patients received a further consolidation cycle with clofarabine at 22.5 mg/m² and cytarabine at 1 g/m² day 1–4. Among the 47 patients, 24/47 (51%) achieved a complete remission, 5/47 (10.5%) a partial response, 10/47 (21%) had a resistant disease, and 6/47 (13%) died of complications during the aplastic phase. The most frequent nonhematologic adverse events were vomiting, diarrhea, transient liver toxicity, febrile neutropenia, and infections microbiologically documented. Among the 24 patients who obtained a CR 13 underwent allogeneic bone marrow transplantation. In 14 patients, complete remission duration was shorter than 12 months, whereas 10 patients experienced longer complete remission duration. These very preliminary results suggest that clofarabine‐cytarabine regimen is effective in this particularly poor prognosis category of patients, representing a potential “bridge” toward bone marrow transplant procedures. Safety data were consistent with previously reported salvage therapies. Further studies and a longer follow up are warranted. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.     

Results of induction and consolidation treatment with intermediate and high-dose cytosine arabinoside and m-Amsa of patients with poor-risk acute myelogenous leukaemia

50 patients (aged 18-58 years) with acute myelogenous leukaemia after a preleukaemic phase (n = 14), acute myelogenous leukaemia that previously failed to respond to conventional chemotherapy (n = 9) or relapsed disease (n = 27) were given remission induction therapy consisting of cytosine arabinoside (1 g/m2 q 12 h x 12) and m-Amsa (115 mg/m2 for 1 or 3 days). Overall, 27 patients (54%) achieved complete remission. The complete remission rate for patients with acute myelogenous leukaemia after a preleukaemic phase (7/14) and those with primary refractory or relapsed leukaemia (20/36) seems superior to that obtained with conventional remission-induction therapy. 12 patients received 1-3 courses of consolidation chemotherapy with cytosine arabinoside (3 g/m2 q 12 h x 8) and m-Amsa (115 mg/m2 for 1 d). 3 of them subsequently underwent autologous bone marrow transplantation. The median duration of remission for the remaining 9 patients was 8 months. 11 patients did not receive consolidation therapy; their median duration of remission was 3 months. The difference between the two groups was not significant. 4 patients underwent allogeneic bone marrow transplantation after achievement of complete remission. The impact of high-dose cytosine arabinoside consolidation chemotherapy on poor-risk acute myelogenous leukaemia remains unclear.     

Continuous-infusion diaziquone in acute myeloid leukemia: a Southeastern Cancer Study Group trial

Diaziquone (AZQ) is a synthetic quinone with considerable activity against L1210 leukemia and potent myelosuppressive activity in man. To test the efficacy and toxicity of AZQ administered by continuous infusion, a phase II multi-institutional trial was undertaken by the Southeastern Cancer Study Group. Eligible adults with acute myeloid leukemia (AML) received AZQ at a dose of 28 mg/m2 daily by continuous infusion for 5 days. Patients failing to achieve complete remission received a second course utilizing the same dose and schedule. Of 25 evaluable patients with relapsed or refractory AML, three achieved complete response (12%) and two achieved partial response (8%). All patients experienced marked myelosuppression. Severe or life-threatening infection was observed in 15 (56%) patients. Clinical or postmortem evidence of central nervous system hemorrhage was encountered in three (12%) patients with severe refractory thrombocytopenia. Minimal nonhematologic toxicity was observed, suggesting that further studies of this agent in combination regimens and possibly for marrow transplantation preparation in patients with acute leukemia are warranted.     

Non-myeloablative hematopoietic stem cell transplantation is of limited value in advanced or refractory acute myeloblastic leukemia. The Mexican experience

Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective strategy for preventing relapse of acute myelogenous leukemia (AML). We analyzed the outcome of 31 primary AML patients who received a reduced-intensity conditioning regimen for allogeneic HSCT in first or second remission. Thirty-one AML patients, 20 in first complete remission (FCR), 8 in second complete remission (SCR) and 3 in a partial remission (SPR) were included. All received busulfan 4 mg/kg/d/2 days, fludarabine 30 mg/m(2)/d/3 days and cyclophosphamide 350 mg/m(2)/d/3 days as conditioning regimen. The median number of CD34+ cells infused was 5.6 x 10(6)/kg and 5.2 x 10(6) in FCR and SCR group, respectively. All patients received cyclosporine-A (CsA) and methotrexate as graft vs. host disease (GvHD) prophylaxis. All patients showed myeloid engraftment (neutrophils >0.5 x 10(9)/l) after a median of 13 days in FCR group and 15 days in SCR group. Platelet recovery >20 x 10(9)/l was achieved after a median of 13 days in both groups. Relapse for 20 patients in FCR was 35% compared to 91% for 11 in SCR/SPR (p < 0.05). Conclusions. Reduced-intensity conditioning followed by allogeneic HSCT can induce stable remission in primary AML patients transplanted in FCR. A high relapse rate was documented in patients with refractory or relapsed AML.     

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.     

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.     

Combined ifosfamide, etoposide and oxalipatin chemotherapy, a low-toxicity regimen for first-relapsed or refractory Hodgkin lymphoma after ABVD/EBVP: a prospective monocentre study on 34 patients

Around 20% of Hodgkin lymphoma (HL) patients are refractory to first‐line therapy with ABVD (adriamycin–bleomycin–vinblastine–dacarbazine) or relapse after complete remission. Salvage regimens frequently have delayed courses or require dose‐reduction because of haemotoxicity. We evaluated the IVOx (ifosfamide–etoposide–oxaliplatin) salvage regimen in terms of response rate, toxicity and stem‐cell mobilization. Thirty‐four patients with relapsed/refractory HL after anthracycline‐containing chemotherapy prospectively received IVOx, consisting of ifosfamide (1500 mg/m² days 1–3), etoposide (150 mg/m² days 1–3) and oxaliplatin (130 mg/m² day 1). Patients <65 years old received high‐dose therapy followed by autologous stem‐cell transplantation (HDT–ASCT). Response was assessed by computed and positron‐emission tomographies. Overall and complete response rates were 76% and 32%, respectively, after 2 cycles. Three episodes of febrile neutropenia occurred, and three patients required dose‐reductions. Twenty‐six patients underwent HDT–ASCT. With median follow‐up at 5 years, the 5‐year overall and event‐free survival rates were 74% and 63%, respectively. IVOx is a well‐tolerated outpatient regimen for relapsed HL, that does not hamper stem‐cell mobilization, achieves good response rates and compares favourably with previously published salvage regimens.     

Low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (CAG regimen) for previously treated patients with relapsed or primary resistant acute myelogenous leukemia (AML) and previously untreated elderly patients with AML, secondary AML, and refractory anemia with excess blasts in transformation

We used the CAG regimen (low-dose cytarabine [10 mg/m2 per 12 hours, days 1-14], aclarubicin [14 mg/m2 per day, days 1-4], and granulocyte colony-stimulating factor [200 micrograms/m2 per day, days 1-14]) for the treatment of patients with primary resistant acute myelogenous leukemia (AML) and previously untreated elderly patients with AML, secondary AML, and refractory anemia with excess blasts in transformation (RAEB-T) in addition to relapsed AML. Forty-three of 69 (62%) patients achieved complete remission (CR), including 29 of 35 (83%) patients with relapsed AML, 1 of 8 patients with primary resistant AML, 5 of 8 elderly patients with previously untreated AML, and 8 of 18 patients with previously untreated secondary AML or RAEB-T. Ten of 22 (45%) patients > or = 65 years old achieved CR. The patients who achieved CR received at least 1 course of modified CAG therapy as the first consolidation therapy, followed by various second consolidation and intensification therapies. The median disease-free survival and overall survival were 8 and 15 months, respectively, for relapsed AML; 11 and 8 months for the elderly patients; and 8 and 17 months for secondary AML and RAEB-T. Myelosuppression was mild to moderate, and other than fever, severe nonhematologic toxicity was rare. CAG as the induction therapy seems promising for the treatment of various categories of poor-prognosis AML.     

Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia

Despite progress in leukemia therapy, most children who experience relapse have a dismal prognosis. New, effective approaches are needed. We conducted a phase 1 study of a novel nucleoside analog, clofarabine, in pediatric patients with refractory and relapsed leukemia. Clofarabine was infused intravenously over 1 hour each day for 5 days. Six dose levels, between 11.25 and 70 mg/m(2) per day for 5 days, were studied in 25 patients. A modified 3 + 3 phase 1 design was followed with 30% dose escalation until the dose-limiting toxicity (DLT) was defined. The maximum tolerated dose (MTD) was 52 mg/m(2) per day for 5 days. At the end of infusion at MTD, clofarabine triphosphate levels in leukemia blasts varied between 6 microM and 19 microM, which resulted in complete and sustained inhibition of DNA synthesis. The DLT was reversible hepatotoxicity and skin rash at 70 mg/m(2) per day for 5 days. Twenty-five patients were treated. Five patients achieved complete remission (CR), and 3 achieved partial remission (PR), for an overall response rate of 32%. Clofarabine is well tolerated and shows significant antileukemic activity in heavily pretreated children. Multicenter phase 2 trials in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are ongoing.     

A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia

The feasibility of combining gemtuzumab ozogamicin (GO) with intensive chemotherapy as first-line treatment of acute myeloid leukemia (AML) was assessed in 72 patients, aged 17 to 59 years, as a prelude to the United Kingdom Medical Research Council (MRC) AML15 trial. Sixty-four patients received induction chemotherapy (DAT [daunorubicin, ara-C, thioguanine], DA [daunorubicin, ara-C], or FLAG-Ida [fludarabine, ara-C, G-CSF, idarubicin]) with GO on day 1. It was possible to give GO 3 mg/m2 with course 1, but 6 mg/m2 with course 1 or GO in a dose of 3 mg/m2 with consecutive courses was not feasible because of hepatotoxicity and delayed hematopoietic recovery. Thirty-one patients who were treated in consolidation with MACE (amsacrine, ara-C, etoposide) or HidAC (HidAC) and GO (3 mg/m2), and 23 in induction and consolidation, tolerated GO (3 mg/m2) well. Grade 4 liver toxicity and sinusoidal obstructive syndrome was more common in thioguanine-containing schedules (P =.007). Remission with course 1 was seen in 86% of patients. DA or FLAG-Ida with GO in induction achieved complete remission in 91% of patients and 78% of these patients are in continuous complete remission at 8 months. GO given with induction (DA or FLAG-Ida) and consolidation (MACE or HidAC) was well tolerated. These schedules are now being compared in the MRC AML15 trial in patients younger than 60 years.     

Control of advanced and refractory acute myelogenous leukaemia with sirolimus-based non-myeloablative allogeneic stem cell transplantation

Non-myeloablative conditioning has extended the use of allogeneic haematopoietic transplant to many previously ineligible patients. We added the immunosuppressive and antitumour agent sirolimus (rapamycin) to an established transplant regimen of fludarabine 25 mg/m(2) days -7 through -3 and cyclophosphamide 1000 mg/m(2) days -7 and -6, with tacrolimus and methotrexate immunoprophyllaxis. A total of 23 patients with acute myelogenous leukaemia (AML) were treated, with a median age of 59 years (range: 28-72) at transplant. Only seven patients in total were in complete remission prior to transplantation. Nine patients were in chemotherapy-refractory progression and seven were primarily refractory to induction therapy. Six patients received matched sibling, 11 unrelated donor, 1-5/6 matched and five haploidentical (haplo - three of six or four of six matched) transplants. The haplo-recipients also received antithymocyte globulin, all patients engrafted. Only two, both recipients of haploidentical cells, have died from transplant-related causes. Twelve of 23 patients survived at 198-1162-d post-transplant (median 578). Four of 12 survivors relapsed at 83, 88, 243 and 508 d and three were in remission after chemotherapy and donor lymphocyte infusion. Although follow up is short, this data suggests that non-myeloablative haematopoietic cell transplantation with sirolimus (rapamycin)-based immunosuppression may provide disease control over several years in some patients with advanced and poor prognosis AML.     

Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia

We conducted a phase 2 study of ruxolitinib in patients with relapsed/refractory leukemias. Patients with acceptable performance status (0-2), adequate organ function, and no active infection, received ruxolitinib 25 mg orally twice a day for 4 weeks (1 cycle). Response was assessed after every 2 cycles of treatment, and patients who completed 2 cycles were allowed to continue treatment until disease progression. Dose escalation to 50 mg twice daily was permitted in patients demonstrating a benefit. Thirty-eight patients, with a median age of 69 years (range, 45-88), were treated. The median number of prior therapies was 2 (range, 1-6). Twelve patients had JAK2V617F mutation. Patients received a median of 2 cycles of therapy (range, 1-22). Three of 18 patients with postmyeloproliferative neoplasm (MPN) acute myeloid leukemia (AML) showed a significant response; 2 achieved complete remission (CR) and one achieved a CR with insufficient recovery of blood counts (CRi). The responding patients with palpable spleens also had significant reductions in spleen size. Overall, ruxolitinib was very well tolerated with only 4 patients having grade 3 or higher toxicity. Ruxolitinib has modest antileukemic activity as a single agent, particularly in patients with post-MPN AML. The study was registered at www.clinicaltrials.gov as NCT00674479.