Clofarabine Does Not Negatively Impact the Outcomes of Patients With Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation

BackgroundClofarabine is actively being investigated as a component of frontline chemotherapy for acute myeloid leukemia (AML). Hepatotoxicity is 1 of the primary adverse events associated with clofarabine and can occasionally can include severe venoocclusive disease (VOD).Patients and MethodsMany patients with AML undergo allogeneic stem cell transplantation (allo-SCT), a procedure that is also associated with hepatotoxicity. We identified AML patients undergoing allo-SCT and stratified them according to whether they received clofarabine-containing (clofarabine, idarubicin, and cytarabine [CIA]) or non–clofarabine-containing cytarabine-based induction/consolidation chemotherapy (idarubicin and cytarabine [ara-C] [IA]). We compared both groups for differences in posttransplantation hepatotoxicity, VOD, and other transplantation outcomes. Forty-two patients were identified (20 receiving CIA and 22 receiving IA). Patient and transplant characteristics were similar. All patients receiving clofarabine-based treatment received CIA within 2.5 months of their allo-SCT.ResultsThere was no difference in the incidence of VOD in the 30 days after transplantation (0 CIA, 1 IA; P = 1.0). Rates of grade 3/4 hepatotoxicity also did not differ between groups. Acute graft-versus-host disease (GVHD), early relapse, and survival were also not significantly different.ConclusionsWe conclude that clofarabine-containing chemotherapy does not adversely impact the outcome of allo-SCT. Specifically, it does not predispose patients to an increased risk of hepatotoxicity, VOD, GVHD, or relapse.     

Superior outcome with hypomethylating therapy in patients with acute myeloid leukemia and high‐risk myelodysplastic syndrome and chromosome 5 and 7 abnormalities

BACKGROUND:

Outcome of patients with acute myeloid leukemia (AML) and high‐risk myelodysplastic syndrome (MDS) with chromosome 5 and 7 abnormalities (excluding del 5[q]) has been poor, with <10% of patients alive at 2 years.

METHODS:

The authors investigated whether treatment with hypomethylating agents (5‐azacytidine/decitabine) leads to an improved outcome. Between January 2004 and December 2007, 81 patients (37 [46%] with AML [≥20% blasts]; 44 [54%] with high‐risk MDS) with chromosome 5 and 7 abnormalities were treated with hypomethylating agents as their initial therapy. These included 68 patients with complex (≥3) abnormalities and 13 with <3 aberrations. During the same period, 151 patients (126 with AML, 25 with MDS) with chromosome 5 and 7 abnormalities (128 complex, 23 noncomplex) were treated with intensive chemotherapy (including cytarabine‐based regimens in 72% and other regimes in 28%).

RESULTS:

The median ages for the 2 groups were 66 years and 61 years, respectively (ranges, 37‐85 years and 19‐89 years). Thirty‐three (41%) patients in the hypomethylating group achieved complete remission (CR) versus 53 (35%) in the chemotherapy group (P = .395). With a median follow‐up of 51 weeks (range, 12‐101 weeks) and 40 weeks (range, 5–128 weeks), 22 of 33 patients in the hypomethylating group and 33 of 53 patients in the chemotherapy group had developed disease recurrence. The median CR duration was 45 weeks and 23 weeks, respectively (P = .153). The overall survival was superior for the hypomethylating group compared with the chemotherapy group (P = .019).

CONCLUSIONS:

Treatment with hypomethylating agents may be superior to chemotherapy in patients with chromosome 5 and 7 abnormalities. Cancer 2009. © 2009 American Cancer Society.     

Treatment of core-binding-factor in acute myelogenous leukemia with fludarabine, cytarabine, and granulocyte colony-stimulating factor results in improved event-free survival

BACKGROUND.

Acute myelogenous leukemia (AML) associated with core‐binding‐factor (CBF) abnormalities is the type of leukemia most responsive to cytarabine (ara‐C) therapy and is of relative favorable prognosis. In vitro and ex vivo observations suggest that increases in intracellular ara‐C levels influenced by administration of fludarabine and granulocyte colony‐stimulating factor (GCSF) increase the effect of ara‐C, prompting us to clinically evaluate the efficacy of such combinations.

METHODS.

We analyzed the event‐free survival of patients with newly diagnosed CBF AML treated with fludarabine and ara‐C (FA) (N = 45) or with FA and GCSF (FLAG) (N = 22) and compared results to patients treated with regimens consisting of idarubicin and ara‐C with or without GCSF (IA/IAG) (N = 47).

RESULTS.

After accounting for prognostic covariates other than treatment (including year in which treatment was administered), FA, and in particular FLAG, were associated with longer event‐free survival than IA/IAG.

CONCLUSIONS.

Thus, our data lends clinical credence to the observed modulation of ara‐C by fludarabine and GCSF. Cancer 2008. © 2008 American Cancer Society.     

Results of the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen in elderly patients with acute lymphocytic leukemia

BACKGROUND.

Understanding the causes of failure in older patients with acute lymphocytic leukemia (ALL) may help improve treatment strategies for patients in this particular age group.

METHODS.

The objectives of the current study were to define the causes of death in older patients (aged ≥60 years) with ALL during induction and consolidation‐maintenance with a dose‐intensive regimen of alternating 8 courses of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper‐CVAD) with high doses of methotrexate and cytarabine followed by maintenance with 6‐mercaptopurine, vincristine, methotrexate, and prednisone and to compare their outcomes with the outcomes of older patients who received earlier, less intensive regimens and younger patients who received hyper‐CVAD. One hundred twenty‐two older patients who received hyper‐CVAD were compared with 34 older patients who received less intensive regimens and with 409 younger patients who received hyper‐CVAD.

RESULTS.

The complete response (CR) rates in older patients receiving hyper‐CVAD, older patients receiving other regimens, and younger patients receiving hyper‐CVAD were 84%, 59%, and 92%, respectively (P < .001); and the respective induction mortality rates were 10%, 12%, and 2% (P not significant in older patients). The incidence of disease resistance during induction was 5%, 27%, and 2%, respectively (P < .001). The majority of deaths were related to infections. Among patients who achieved a CR, death in CR was noted in 34%, 15%, and 7% of older patients receiving hyper‐CVAD, older patients receiving other regimens, and younger patients, respectively (P < .001); and the respective rates of recurrence were 40%, 80%, and 48% (P = .004). The estimated 5‐year survival rates were 20%, 9%, and 48%, respectively (P < .001).

CONCLUSIONS.

The results of the current study suggested that intensifying the chemotherapy in older patients with ALL reduced the incidence of leukemia resistance but increased the incidence of death in CR from myelosuppression‐associated infections. The overall benefit:risk ratio was favorable. Identifying novel, low‐intensity agents/regimens for older patients with ALL may improve the results further. Cancer 2008. © 2008 American Cancer Society.     

Time to platelet recovery predicts outcome of patients with de novo acute lymphoblastic leukaemia who have achieved a complete remission

Survival in acute leukaemia depends on the achievement of complete remission (CR). However, CR is not a clear-cut phenomenon and certain variables of its definition could more accurately characterize the quality of the remission. Because platelet recovery > 100 x 10(9)/l is an essential component of CR in acute leukaemia, we hypothesized that time to platelet recovery (TPR) might be predictive of overall survival (OS) or disease-free survival (DFS) in acute lymphoblastic leukaemia (ALL). We analysed TPR in 249 patients with ALL who entered CR after one course of induction chemotherapy and correlated TPR with DFS and OS. TPR was significantly associated with both DFS and OS if it occurred within a maximum of about 60 d from start of therapy. Furthermore, during that time period, the relative risk of death increased with increasing TPR. Although presence of the Philadelphia chromosome was the single most important adverse feature at diagnosis, the effect of TPR on survival continued to be significant within this patient subgroup. This effect was so pronounced that Philadelphia chromosome-positive patients with a TPR of 12 d had a better outcome than Philadelphia chromosome-negative patients with a TPR of 48 d. Thus, a short TPR seems to be able to override adverse characteristics in the outcome of ALL patients treated with chemotherapy. We conclude that a quicker TPR predicts longer DFS and OS in patients with ALL. As platelet counts are obtained almost daily in patients undergoing chemotherapy, TPR can readily be utilized to assess the prognosis of these patients.     

A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome

We previously reported the feasibility of clofarabine and cytarabine combinations in AML. Questions remain as to (1) the therapeutic advantage of this combination and (2) the role of lower doses of clofarabine and cytarabine in older patients. We have conducted an adaptively randomized study of lower-dose clofarabine with or without low-dose cytarabine in previously untreated patients with AML aged 60 years and older. Patients received 30 mg/m(2) clofarabine intravenously daily for 5 days with or without 20 mg/m(2) cytarabine subcutaneously daily for 14 days as induction. Consolidation consisted of 3 days of clofarabine with or without 7 days of cytarabine. Seventy patients were enrolled. The median age was 71 years (range, 60-83 years). Sixteen patients received clofarabine and 54 the combination. Overall, 56% achieved complete remission (CR). CR rate was significantly higher with the combination (63% vs 31%; P = .025). Induction mortality was 19% with the combination versus 31% with clofarabine alone (P = .276). The combination showed better event-free survival (7.1 months vs 1.7 months; P = .04), but not overall survival (11.4 months vs 5.8 months; P = .1). Clofarabine plus low-dose cytarabine has a higher response rate than clofarabine alone with comparable toxicity. This trial is registered at www.clinicaltrials.gov as no. NCT00088218.     

Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma

Therapy of lymphoblastic lymphoma (LL) has evolved with use of chemotherapy regimens modeled after those for acute lymphocytic leukemia (ALL). We treated 33 patients with LL with the intensive chemotherapy regimens hyper-CVAD (fractionated cyclophosphamide, vincristine, Adriamycin, and dexamethasone) or modified hyper-CVAD used for ALL at our institution. Induction consolidation was administered with 8 or 9 alternating cycles of chemotherapy over 5 to 6 months with intrathecal chemotherapy prophylaxis, followed by maintenance therapy. Consolidative radiation therapy was given to patients with mediastinal disease at presentation. No consolidation with autologous or allogeneic stem cell transplantation was performed. At diagnosis, 80% were T-cell immunophenotype, 70% were stages III to IV, 70% had mediastinal involvement, and 9% had central nervous system (CNS) disease. Of the patients, 30 (91%) achieved complete remission, and 3 (9%) achieved partial response. Within a median of 13 months, 10 patients (30%) relapsed or progressed. Estimates for 3-year progression-free and overall survival for the 33 patients were 66% and 70%, respectively. Estimates for the patients with known T-cell immunophenotype were 62% and 67%, respectively. No parameters (eg, age, stage, serum lactate dehydrogenase [LDH], beta(2) microglobulin) appeared to influence outcome except for CNS disease at presentation. Modification of the hyper-CVAD regimen with anthracycline intensification did not improve outcome. Other modifications of the program could include incorporation of monoclonal antibodies and/or nucleoside analogs, particularly for slow responders or those with residual mediastinal disease.