Reversing the multidrug resistance in acute leukemia: Until the leukemia initiating cell?

Reversal of drug resistance is of pivotal importance in order to improve the results of chemotherapy. Monitoring of such reversal is necessary in order to analyze the results of clinical trials. Nonetheless, the leukemia cell population to eradicate is the leukemia initiating cells characterized by a CD34+CD38- phenotype. The evaluation of novel drug resistance modulators should be performed both in the whole leukemic cell population and in the leukemia initiating cell compartment, that is responsible for "mature" leukemia cells replenishment.     

Can we incorporate geriatric assessment in the management of acute lymphoblastic leukemia in older adults?

Acute lymphoblastic leukemia (ALL) is an uncommon disease. Approximately 14% of new ALL cases occur in adults aged 60 and over, and the three-year overall survival in this population is poor at 12.8%. Older adults with ALL are heterogeneous in terms of their underlying health status, which can make treatment selection challenging given the disease rarity and limited inclusion of older patients in clinical trials. A comprehensive geriatric assessment (CGA) is a compilation of tools to assess multiple domains such as physical function and cognition, and may assist in guiding treatment selection and supportive care interventions. However, studies on the use of CGA are limited in older adults with ALL. In this review, we discuss the utility of CGA in patients with various hematologic malignancies. Using two patient cases of ALL, we also describe how CGA may be use to guide treatment and supportive care interventions.     

Comparison of the intracellular pharmacokinetics of doxorubicin and 4′-epi-doxorubicin in patients with acute leukemia

Summary A direct comparison of the intracellular pharmacokinetics of 4-epi-doxorubicin and doxorubicin was carried out in five patients with leukemia who were given weekly low doses of a combination of these drugs at 20 mg each in an i.v. injection. Blood samples were collected for 48 h after administration and the drug concentrations in leukemic cells were determined by high-performance liquid chromatography (HPLC). The intracellular peak concentrations of 4-epi-doxorubicin were higher than those of doxorubicin in all patients. The AUC for the intracellular drug concentration vs time curve was significantly higher for 4-epi-doxorubicin. The intracellular uptake and retention were also studied in vitro after incubation of isolated leukemic blast cells with the two drugs; they showed the same pattern observed in vivo. We conclude that 4-epi-doxorubicin and doxorubicin exhibit different pharmacokinetics in malignant cells. The therapeutic significance of this finding requires further evaluation.     

Evaluation of the detection of PML-RARα fusion gene in acute promyelocytic leukemia to monitor minimal residual disease

Objective To investigate the kinetics of PML-RARα fusion gene in acute promyelocytic leukemia(APL)to monitor minimal residual disease(MRD). Methods In induction therapy,consolidation and maintenance therapy courses, PML-RARα fusion gene was performed by RT-PCR. Results The long-term follow-up of 18 cases achieved complete remission (CR),two cases experienced molecular relapse. One case relapsed at 4 months after CR1 and achieved CR2 after induction therapy. However, molecular and hematology relapsed again at 2 months after CR2 and re-achieved CR3. The other case relapsed at 74 months after CR1 and achieved CR2 after induction treatment, who had survived for 106 months until the end of follow-up. Conclusion RT-PCR assay for detection of PML-RARα should be performed regularly during CR period so as to find molecular relapse eady. Hematological relapse could potentially be averted through treatment modification according to molecular monitoring results of PML-RARα.     

Evaluation of the detection of PML-RARα fusion gene in acute promyelocytic leukemia to monitor minimal residual disease

Objective To investigate the kinetics of PML-RARα fusion gene in acute promyelocytic leukemia(APL)to monitor minimal residual disease(MRD). Methods In induction therapy,consolidation and maintenance therapy courses, PML-RARα fusion gene was performed by RT-PCR. Results The long-term follow-up of 18 cases achieved complete remission (CR),two cases experienced molecular relapse. One case relapsed at 4 months after CR1 and achieved CR2 after induction therapy. However, molecular and hematology relapsed again at 2 months after CR2 and re-achieved CR3. The other case relapsed at 74 months after CR1 and achieved CR2 after induction treatment, who had survived for 106 months until the end of follow-up. Conclusion RT-PCR assay for detection of PML-RARα should be performed regularly during CR period so as to find molecular relapse eady. Hematological relapse could potentially be averted through treatment modification according to molecular monitoring results of PML-RARα.     

Evaluation of the detection of PML-RARα fusion gene in acute promyelocytic leukemia to monitor minimal residual disease

Objective To investigate the kinetics of PML-RARα fusion gene in acute promyelocytic leukemia(APL)to monitor minimal residual disease(MRD). Methods In induction therapy,consolidation and maintenance therapy courses, PML-RARα fusion gene was performed by RT-PCR. Results The long-term follow-up of 18 cases achieved complete remission (CR),two cases experienced molecular relapse. One case relapsed at 4 months after CR1 and achieved CR2 after induction therapy. However, molecular and hematology relapsed again at 2 months after CR2 and re-achieved CR3. The other case relapsed at 74 months after CR1 and achieved CR2 after induction treatment, who had survived for 106 months until the end of follow-up. Conclusion RT-PCR assay for detection of PML-RARα should be performed regularly during CR period so as to find molecular relapse eady. Hematological relapse could potentially be averted through treatment modification according to molecular monitoring results of PML-RARα.     

Evaluation of the detection of PML-RARα fusion gene in acute promyelocytic leukemia to monitor minimal residual disease

Objective To investigate the kinetics of PML-RARα fusion gene in acute promyelocytic leukemia(APL)to monitor minimal residual disease(MRD). Methods In induction therapy,consolidation and maintenance therapy courses, PML-RARα fusion gene was performed by RT-PCR. Results The long-term follow-up of 18 cases achieved complete remission (CR),two cases experienced molecular relapse. One case relapsed at 4 months after CR1 and achieved CR2 after induction therapy. However, molecular and hematology relapsed again at 2 months after CR2 and re-achieved CR3. The other case relapsed at 74 months after CR1 and achieved CR2 after induction treatment, who had survived for 106 months until the end of follow-up. Conclusion RT-PCR assay for detection of PML-RARα should be performed regularly during CR period so as to find molecular relapse eady. Hematological relapse could potentially be averted through treatment modification according to molecular monitoring results of PML-RARα.     

Evaluation of the detection of PML-RARα fusion gene in acute promyelocytic leukemia to monitor minimal residual disease

Objective To investigate the kinetics of PML-RARα fusion gene in acute promyelocytic leukemia(APL)to monitor minimal residual disease(MRD). Methods In induction therapy,consolidation and maintenance therapy courses, PML-RARα fusion gene was performed by RT-PCR. Results The long-term follow-up of 18 cases achieved complete remission (CR),two cases experienced molecular relapse. One case relapsed at 4 months after CR1 and achieved CR2 after induction therapy. However, molecular and hematology relapsed again at 2 months after CR2 and re-achieved CR3. The other case relapsed at 74 months after CR1 and achieved CR2 after induction treatment, who had survived for 106 months until the end of follow-up. Conclusion RT-PCR assay for detection of PML-RARα should be performed regularly during CR period so as to find molecular relapse eady. Hematological relapse could potentially be averted through treatment modification according to molecular monitoring results of PML-RARα.     

Evaluation of the detection of PML-RARα fusion gene in acute promyelocytic leukemia to monitor minimal residual disease

Objective To investigate the kinetics of PML-RARα fusion gene in acute promyelocytic leukemia(APL)to monitor minimal residual disease(MRD). Methods In induction therapy,consolidation and maintenance therapy courses, PML-RARα fusion gene was performed by RT-PCR. Results The long-term follow-up of 18 cases achieved complete remission (CR),two cases experienced molecular relapse. One case relapsed at 4 months after CR1 and achieved CR2 after induction therapy. However, molecular and hematology relapsed again at 2 months after CR2 and re-achieved CR3. The other case relapsed at 74 months after CR1 and achieved CR2 after induction treatment, who had survived for 106 months until the end of follow-up. Conclusion RT-PCR assay for detection of PML-RARα should be performed regularly during CR period so as to find molecular relapse eady. Hematological relapse could potentially be averted through treatment modification according to molecular monitoring results of PML-RARα.     

Evaluation of the detection of PML-RARα fusion gene in acute promyelocytic leukemia to monitor minimal residual disease

Objective To investigate the kinetics of PML-RARα fusion gene in acute promyelocytic leukemia(APL)to monitor minimal residual disease(MRD). Methods In induction therapy,consolidation and maintenance therapy courses, PML-RARα fusion gene was performed by RT-PCR. Results The long-term follow-up of 18 cases achieved complete remission (CR),two cases experienced molecular relapse. One case relapsed at 4 months after CR1 and achieved CR2 after induction therapy. However, molecular and hematology relapsed again at 2 months after CR2 and re-achieved CR3. The other case relapsed at 74 months after CR1 and achieved CR2 after induction treatment, who had survived for 106 months until the end of follow-up. Conclusion RT-PCR assay for detection of PML-RARα should be performed regularly during CR period so as to find molecular relapse eady. Hematological relapse could potentially be averted through treatment modification according to molecular monitoring results of PML-RARα.     

Treatment of adults with acute lymphoblastic leukemia: Do the specifics of the regimen matter?

BACKGROUND:

Induction therapy for adults with acute lymphoblastic leukemia (ALL) is similar across essentially all regimens, comprised of vincristine, corticosteroids, and anthracyclines intensified with cyclophosphamide, asparaginase, or both. Given the lack of randomized data, to date, no regimen has emerged as standard. The authors previously evaluated cytarabine 3 g/m² daily for 5 days with mitoxantrone 80 mg/m² (the ALL‐2 regimen) as a novel induction regimen. Compared with historic controls, the ALL‐2 regimen was superior in terms of incidence of complete remission, failure with resistant disease, and activity in patients with Philadelphia chromosome (Ph)‐positive ALL.

METHODS:

The authors conducted a multicenter, prospective, randomized trial of the ALL‐2 regimen compared with a standard 4‐drug induction (the L‐20 regimen). Patients also received consolidation, maintenance therapy, and central nervous system prophylaxis. The trial accrued patients from August 1996 to October 2004.

RESULTS:

The median follow‐up for survivors was 7 years, and the median patient age was 43 years. Responses were evaluated in 164 patients. The treatment arms were balanced in terms of pretreatment characteristics. The frequency of complete remission for the ALL‐2 regimen versus the L‐20 regimen was 83% versus 71% (P = .06). More patients on the L‐20 arm failed with resistant disease (21% vs 8%; P = .02). Induction deaths were comparable at 9% (ALL‐2) versus 7% (L‐20). The median survival was similar; and, at 5 years, the survival rate was 33% alive on the ALL‐2 arm versus 27% on the L‐20.

CONCLUSIONS:

Despite superior results of induction therapy with the ALL‐2 regimen, this treatment did not improve long‐term outcomes. When coupled to the reported experience of other studies in adults with ALL, the results of this randomized trial raise the possibility that ultimate outcomes in adult ALL may be independent of the specific regimen chosen. Cancer 2013. © 2012 American Cancer Society.     

Are two courses of chemotherapy required in phase II trials in acute leukemia?

In most phase II studies, patients must receive two courses of chemotherapy in order to be judged evaluable for response. We reviewed the experience with six different phase II drugs given to patients with acute leukemia and found that the requirement of a second course may be unnecessary. Administration of second courses do not transform "ineffective" drugs into effective drugs. Furthermore, second courses lead to enhanced toxicity. We conclude that future trials with phase II agents in acute leukemia should be limited to the administration of one course.     

Evaluation of the detection of PML-RARα fusion gene in acute promyelocytic leukemia to monitor minimal residual disease

Objective To investigate the kinetics of PML-RARα fusion gene in acute promyelocytic leukemia(APL)to monitor minimal residual disease(MRD). Methods In induction therapy,consolidation and maintenance therapy courses, PML-RARα fusion gene was performed by RT-PCR. Results The long-term follow-up of 18 cases achieved complete remission (CR),two cases experienced molecular relapse. One case relapsed at 4 months after CR1 and achieved CR2 after induction therapy. However, molecular and hematology relapsed again at 2 months after CR2 and re-achieved CR3. The other case relapsed at 74 months after CR1 and achieved CR2 after induction treatment, who had survived for 106 months until the end of follow-up. Conclusion RT-PCR assay for detection of PML-RARα should be performed regularly during CR period so as to find molecular relapse eady. Hematological relapse could potentially be averted through treatment modification according to molecular monitoring results of PML-RARα.     

Chronic myeloid leukemia in the tyrosine kinase inhibitor era: What is the best therapy?

Imatinib mesylate, 400 mg/d, is considered standard therapy for managing patients with chronic myeloid leukemia (CML) in chronic phase, yielding high rates of cytogenetic responses that translate into favorable long-term outcomes. However, some patients do not achieve adequate levels of response, lose a previously acquired response, or are forced to discontinue imatinib therapy because of safety reasons. To avoid these outcomes, several approaches are being tested in the frontline setting, including the use of higher imatinib doses or second-generation tyrosine kinase inhibitors such as nilotinib or dasatinib, the latter of which is approved only for managing patients who have imatinib therapy failure. Newer multikinase inhibitors active against multiple ABL1 mutations are also under development for patients in any CML phase who have therapy failure on sequential imatinib and a second-generation tyrosine kinase inhibitor or carry the highly resistant T315I mutation and are not candidates for allogeneic stem cell transplantation. Some of these approaches are expected to improve the outcomes of patients with CML.     

Regulation of HIF-1α signaling and chemoresistance in acute lymphocytic leukemia under hypoxic conditions of the bone marrow microenvironment

Overcoming resistance to chemotherapy is the main therapeutic challenge in the treatment of acute lymphocytic leukemia (ALL). Interactions between leukemia cells and the microenvironment promote leukemia cell survival and confer resistance to chemotherapy. Hypoxia is an integral component of bone marrow (BM) microenvironment. Hypoxia-inducible factor-1α (HIF-1), a key regulator of the cellular response to hypoxia, regulates cell growth and metabolic adaptation to hypoxia. HIF-1α expression, analyzed by Reverse Phase Protein Arrays in 92 specimens from newly diagnosed patients with pre-B-ALL, had a negative prognostic impact on survival (p = 0.0025). Inhibition of HIF-1α expression by locked mRNA antagonist (LNA) promoted chemosensitivity under hypoxic conditions, while pharmacological or genetic stabilization of HIF-1α under normoxia inhibited cell growth and reduced apoptosis induction by chemotherapeutic agents. Co-culture of pre-B ALL or REH cells with BM-derived mesenchymal stem cells (MSC) under hypoxia resulted in further induction of HIF-1α protein and acquisition of the glycolytic phenotype, in part via stroma-induced AKT/mTOR signaling. mTOR blockade with everolimus reduced HIF-1α expression, diminished glucose uptake and glycolytic rate and partially restored the chemosensitivity of ALL cells under hypoxia/stroma co-cultures. Hence, mTOR inhibition or blockade of HIF-1α-mediated signaling may play an important role in chemosensitization of ALL cells under hypoxic conditions of the BM microenvironment.