Phase I study of sorafenib in patients with refractory or relapsed acute leukemias

Background

Sorafenib is a multi-kinase inhibitor with activity against fms-like tyrosine kinase 3 with internal tandem duplication mutation and Raf kinase among others. A phase I dose escalation study of sorafenib was conducted in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias.

Design and Methods

Fifty patients received one of two different schedules; Schedule “A”: once or twice daily, five days per week, every week for a 21 day cycle, and Schedule “B”: once or twice daily, for 14 days every 21 days. Dose limiting toxicities were grade 3/4 hypertension, hyperbilirubinemia, and amylase elevation. The recommended phase II dose in hematologic malignancies is 400 mg twice daily for both schedules.

Results

Complete remissions or complete remissions with incomplete recovery of platelets were achieved in 5 (10%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Significant reduction in bone marrow and/or peripheral blood blasts was seen in an additional 17 (34%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Eleven of these responses (including 3 complete remissions/complete remissions with incomplete recovery) lasted for 2 cycles or beyond. In conclusion, sorafenib is active and well tolerated in acute myelogenous leukemia with fms-like tyrosine kinase 3 internal tandem duplication mutation.

Conclusions

Additional studies of sorafenib in patients with acute myelogenous leukemia, particularly those with fms-like tyrosine kinase 3 internal tandem duplication, are warranted, including sorafenib-based combinations. (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00217646","term_id":"NCT00217646"}}NCT00217646)     

Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia

The best initial therapy for elderly patients with chronic lymphocytic leukemia (CLL) has not yet been defined. We investigated the activity of lenalidomide as initial therapy for elderly patients with CLL. Sixty patients with CLL 65 years of age and older received treatment with lenalidomide orally 5 mg daily for 56 days, then titrated up to 25 mg/d as tolerated. Treatment was continued until disease progression. At a median follow-up of 29 months, 53 patients (88%) are alive and 32 patients (53%) remain on therapy. Estimated 2-year progression-free survival is 60%. The overall response rate to lenalidomide therapy is 65%, including 10% complete response, 5% complete response with residual cytopenia, 7% nodular partial response, and 43% partial response. Neutropenia is the most common grade 3 or 4 treatment-related toxicity observed in 34% of treatment cycles. Major infections or neutropenic fever occurred in 13% of patients. Compared with baseline levels, we noted an increase in serum immunoglobulin levels across all classes, and a reduction in CCL3 and CCL4 plasma levels was noted in responding patients. Lenalidomide therapy was well tolerated and induced durable remissions in this population of elderly, symptomatic patients with CLL. This study was registered at www.clinicaltrials.gov as #NCT00535873.     

Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia

This phase I/II study was conducted to determine the maximum tolerated dose, toxicity, and efficacy of clofarabine in combination with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming (GCLAC), in the treatment of patients with relapsed or refractory acute myeloid leukaemia (AML). Dose escalation of clofarabine occurred without dose-limiting toxicity, so most patients were treated at the maximum dose, 25 mg/m(2) per day with cytarabine 2 g/m(2) per day, each for 5 d, and G-CSF 5 μg/kg, beginning the day before chemotherapy and continuing daily until neutrophil recovery. The complete remission (CR) rate among the 46 evaluable patients was 46% (95% confidence interval [CI] 31-61%) and the CR + CR but with a platelet count <100 × 10(9)/l rate was 61% (95% CI 45-75%). Multivariate analysis showed that responses to GCLAC were independent of age, cytogenetic risk category, and number of prior salvage regimens. GCLAC is highly active in relapsed and refractory AML and warrants prospective comparison to other regimens, as well as study in untreated patients.     

Prognostic Factors Associated With Disease Progression and Overall Survival in Patients With Myelodysplastic Syndromes Treated With Decitabine

BackgroundMyelodysplastic syndromes (MDS) progress to acute myeloid leukemia (AML) in approximately 30% of patients. Identification of risk factors for progression to AML and overall survival (OS) would help guide treatment decisions.Patients and MethodsWe investigated prognostic factors for progression to AML and survival in 163 patients with MDS treated with decitabine 15 mg/m² over 3 hours every 8 hours for 3 days every 6 weeks (n = 74) or 20 mg/m² over 1 hour daily for 5 days every 4 weeks (n = 89).ResultsMultivariate analysis of pooled baseline data revealed that only study effect was associated with progression to AML. A hemoglobin value at least 10 g/dL, platelet count at least 50 × 10³/μL, and lack of chromosome 5 or 7 abnormalities were associated with longer OS.ConclusionsPatients with certain prognostic factors should be considered for other interventions in addition to decitabine treatment.     

Burkitt Lymphoma and Atypical Burkitt or Burkitt-like Lymphoma: Should These be Treated as Different Diseases?

Burkitt lymphoma (BL) is a mature B-cell non-Hodgkin lymphoma with an aggressive clinical course. Since the advent of short, intensive, multiagent chemoimmunotherapy regimens, it has carried a favorable prognosis. BL has been rather well characterized, whereas the other lymphomas morphologically resembling it are more heterogeneous. The cases classified as atypical BL/Burkitt-like lymphoma by the 2001 World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissue were thought to represent a continuum between BL and diffuse large B-cell lymphoma (DLBCL). The optimal therapeutic strategy for this provisional entity was not definitively established. However, recent incorporation of molecular genetic data into the 2008 WHO Classification has allowed further refinements with significant therapeutic implications, including the designation of a new provisional entity, “B-cell lymphoma, unclassifiable, with features intermediate between BL and DLBCL.” This review presents a comprehensive overview of the previously designated provisional entity of atypical BL/BLL in conjunction with a detailed comparison with BL and DLBCL.     

Chronic myelomonocytic leukaemia after platinum-based therapy for non-small cell lung cancer: case report and review of the literature

Chronic myelomonocytic leukaemia (CMML) is a preleukaemic condition with myeloproliferative features, and classified as a part of myelodysplastic syndrome (MDS). Other than alkylating agents and topoisomerase II inhibitors, there is less evidence that chemotherapeutic drugs are associated with therapy-related CMML, acute leukaemia or MDS. We present a patient who developed CMML within 2 years of platinum-based chemotherapy for a metastatic non-small cell lung cancer. He received a cumulative dose of 240 mg/m(2) of cisplatin, and 1123 mg/m(2) of carboplatin before developing CMML. The cytogenetic study revealed trisomy 8. This is the first reported case that links platinum-based therapy with development of CMML with trisomy 8. Although the relationship between platinum therapy and the development of CMML is difficult to assess due to combinational nature of therapy in most cases, physicians should consider the possibility of CMML in patients with symptoms or signs suggestive of haematologic malignancy after platinum therapy.     

Phase 1 multicenter study of vincristine sulfate liposomes injection and dexamethasone in adults with relapsed or refractory acute lymphoblastic leukemia

BACKGROUND:

Dose intensification of chemotherapy has improved outcome for younger adults with de novo acute lymphoblastic leukemia (ALL). Novel formulations of standard chemotherapy agents may further reduce the incidence of disease recurrence after frontline chemotherapy. Vincristine (VCR) sulfate liposomes injection (VSLI) is a sphingomyelin/cholesterol nanoparticle encapsulated VCR formulation that improves the pharmacokinetic profile of VCR without augmenting neurotoxicity.

METHODS:

A phase 1 trial of weekly, intravenous VSLI at 1.5 mg/m², 1.825 mg/m², 2.0 mg/m², 2.25 mg/m², or 2.4 mg/m² was conducted to determine the maximum tolerated dose (MTD) using a standard, 3 + 3 dose‐escalation design. Dexamethasone (40 mg) was given on Days 1 through 4 and on Days 11 through 14 of each 4‐week cycle.

RESULTS:

Thirty‐six adults with relapsed/refractory ALL, all previously treated with conventional VCR, received at least 1 dose of VSLI. The MTD of VSLI was 2.25 mg/m² based on dose‐limiting toxicities of grade 3 motor neuropathy, grade 4 seizure, and grade 4 hepatotoxicity in 1 patient each at the 2.4 mg/m² dose level. The most common toxicities attributed to VSLI included peripheral neuropathy (55%) and constipation (53%). A complete response (CR) was achieved in 7 of 36 patients (19%) based on an intent‐to‐treat analysis; the CR rate was 29% for the 14 patients who underwent therapy as their first salvage attempt. Four of 7 patients who achieved a CR underwent subsequent allogeneic stem cell transplantation in remission.

CONCLUSIONS:

In this study, VSLI plus dexamethasone appeared to be an effective salvage therapy option for relapsed/refractory ALL. A phase 2, international, multicenter clinical trial assessing the efficacy of single‐agent VSLI as second salvage therapy for patients with previously treated ALL is underway. Cancer 2009. © 2009 American Cancer Society.     

Blood counts at time of complete remission provide additional independent prognostic information in acute myeloid leukemia

Prognostic relevance of blood counts at complete remission (CR) in acute myeloid leukemia (AML) is not clear. To address this issue, we analyzed 891 AML patients in first CR. From the data of randomly selected 446 patients (training set), we first established optimal cutoffs for neutrophil and platelet counts and hemoglobin level at CR in terms of relapse-free survival (RFS). Patients whose counts were higher than each optimal cutoff were shown to have significantly better RFS (p<0.01 for neutrophil and platelets, and p=0.02 for hemoglobin). Then we tested whether these cutoffs were, after accounting for better known prognostic covariates, also predictive of RFS in the remaining 445 patients (validation set). Our data revealed that higher neutrophil count was independently predictive of longer RFS in the validation set (hazard ratio 1.38, p=0.02), as was higher platelet count (hazard ratio 1.35, p=0.04). These findings suggest that blood counts at CR, information readily available, are useful in prognostication in AML.