Early lymphocyte recovery following intensive timed sequential chemotherapy for acute myelogenous leukemia: peripheral oligoclonal expansion of regulatory T cells.
Blood. 2010 Oct 8;
Authors: Kanakry CG, Hess AD, Gocke CD, Thoburn C, Meyer C, Briel J, Luznik L, Smith BD, Levitsky H, Karp JE
Few published studies characterize early lymphocyte recovery after intensive chemotherapy for acute myelogenous leukemia (AML). To test the hypothesis that lymphocyte recovery mirrors ontogeny, we characterized early lymphocyte recovery and attendant cytokine profiles in twenty consecutive patients undergoing induction timed sequential chemotherapy for newly diagnosed AML. Recovering T lymphocytes were predominantly CD4+ and included a greatly expanded population of CD3+CD4+CD25+Foxp3+ T cells. Recovering CD3+CD4+CD25+Foxp3+ T cells were phenotypically activated regulatory T cells and demonstrated suppressive activity on cytokine production in a mixed lymphocyte reaction. Despite an initial burst of thymopoiesis, most recovering regulatory T cells were peripherally derived. Furthermore, regulatory T cells demonstrated marked oligoclonal skewing, suggesting that their peripheral expansion was antigen-driven. Overall, lymphocyte recovery after chemotherapy differs from ontogeny, specifically identifying a peripherally expanded oligoclonal population of activated regulatory T lymphocytes. These differences suggest a stereotyped immunologic recovery shared by the majority of newly diagnosed AML patients after induction timed sequential chemotherapy. A better understanding of this oligoclonal regulatory T cell population will be fundamental towards developing effective immunomodulatory techniques to improve survival for patients with AML.
PMID: 20935254 [PubMed - as supplied by publisher]
Allosteric inhibition of BCR-ABL.
Cell Cycle. 2010 Sep 3;9(18)
Authors: Hassan AQ, Sharma SV, Warmuth M
Impaired regulation of kinase activity can lead to a variety of diseases, including cancer. Inhibition of kinase activity has, therefore, been considered an attractive anti-cancer therapeutic strategy. The success of targeted therapy with kinase inhibitors has been well documented with BCR-ABL, where imatinib specifically inhibits kinase activity with impressive pharmacological responses in chronic myelogenous leukemia (CML). However, the success of kinase inhibitors as cancer therapeutics is being challenged clinically by the emergence of acquired resistance. Most kinase inhibitors available today are ATP-competitive. There have been efforts to develop kinase inhibitors with new modes of action. In this review, we highlight the development of ‘allosteric kinase inhibitors’ that inhibit kinase activity by binding to a site remote from the active site of the kinase. We focus on recent efforts directed towards BCR-ABL, for which, significant progress has been made to develop allosteric inhibitors with promising therapeutic activity, especially in the context of overcoming clinically acquired resistance mutations to the first generation of ATP-competitive kinase inhibitors.
PMID: 20930519 [PubMed - as supplied by publisher]
Decitabine in myelodysplastic syndromes and chronic myelomonocytic leukemia: Argentinian/South Korean multi-institutional clinical experience.
Leuk Lymphoma. 2010 Oct 7;
Authors: Iastrebner M, Jang JH, Nucifora E, Kim K, Sackmann F, Kim DH, Orlando S, Jung CW, Basquiera A, Klein G, Santini F, Bernard HI, Korin J, Taborda G
This multicenter, open-label study evaluated the efficacy and safety of decitabine in patients from Argentina and South Korea with myelodysplastic syndromes or chronic myelomonocytic leukemia. Of 106 patients who received decitabine 20 mg/m<sup>2</sup> intravenously over 1 h once daily for 5 days in 4-week cycles, 99 patients were evaluable after receiving at least two cycles. The overall improvement rate was 35% (19% complete response +4% marrow complete response +4% partial response +8% hematologic improvement). Overall survival at 2 years was 71%. Treatment-related adverse events included febrile neutropenia, thrombocytopenia and bleeding, asthenia, fatigue, and eosinophilia. After complete response (CR), three patients received an allogeneic stem cell transplant. Four patients who relapsed after CR responded to decitabine retreatment. Acute myelogenous leukemia developed during follow-up in 21% of patients. Decitabine in a 5-day outpatient administration schedule was effective and well tolerated in typical clinical practice settings in South America and Asia.
PMID: 20929328 [PubMed - as supplied by publisher]
Pharmacokinetic targeting of intravenous busulfan reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for acute myelogenous leukemia.
J Hematol Oncol. 2010 Oct 6;3(1):36
Authors: Pidala J, Kim J, Anasetti C, Kharfan-Dabaja MA, Nishihori T, Field T, Perkins J, Perez L, Fernandez HF
ABSTRACT: Optimal conditioning therapy for hematopoietic cell transplantation (HCT) in acute myelogenous leukemia (AML) remains undefined. We retrospectively compared outcomes of a consecutive series of 51 AML patients treated with oral busulfan (1mg/kg every 6 hours for 4 days) and cyclophosphamide (60mg/kg IV x 2 days) – (Bu/Cy) with 100 consecutive AML patients treated with pharmacokinetic targeted IV busulfan (AUC < 6000uM/L*min per day x 4 days) and fludarabine (40mg/m2 x 4 days) – (t-IV Bu/Flu). The Bu/Cy and t-IV Bu/Flu groups significantly differed according to donor relation, stem cell source, aGVHD prophylaxis, remission status, primary vs. secondary disease, median age, and % blasts prior to HCT (p < 0.01 for each). Conditioning with t-IV Bu/Flu reduced early toxicity including idiopathic pneumonia syndrome (IPS) and hepatic veno-occlusive disease (VOD). Additionally, the trajectory of early NRM (100 day: 16% vs. 3%, and1 year: 25% vs. 15% for Bu/Cy and t-IV Bu/Flu, respectively) favored t-IV Bu/Flu. Grade II-IV aGVHD (48% vs. 82%, p < 0.0001), as well as moderate/severe cGVHD (7% vs. 40%, p < 0.0001) differed between the Bu/Cy and t-IV Bu/Flu groups, due to the predominance of peripheral blood stem cells in the t-IV Bu/Flu group. Pharmacokinetic targeting of intravenous busulfan in combination with fludarabine is associated with reduced conditioning regimen related toxicity compared to oral busulfan and cyclophosphamide. However, multivariable analysis did not demonstrate significant differences in overall survival (p = 0.78) or non-relapse mortality (p = 0.6) according to conditioning regimen delivered.
PMID: 20925957 [PubMed - as supplied by publisher]
Blast phase of chronic myeloid leukemia presenting lymphoid phenotype with a chronic phase of extremely short duration.
Intern Med. 2010;49(13):1297-301
Authors: Sumimoto H, Tsujimura H, Ise M, Mimura N, Sakai C, Takagi T, Kumagai K
Chronic myeloid leukemia (CML) is generally diagnosed in the chronic phase. We have recently encountered two CML-blastic phase (BP) cases, a 71-year-old woman and a 74-year-old man, who resembled de novo acute leukemia. The complete blood count was normal at least 11 and 13 months before the presentation, respectively. The leukemic cells showed predominant lymphoid phenotype. The blasts and granulocytes were positive for BCR-ABL, indicative of CML-BP. Both patients were successfully treated with prednisone and vincristine, followed by Imatinib. Our cases indicate rare presentations of CML-BP with an extremely short chronic phase. Ph-positive de novo acute leukemia should be carefully distinguished from CML-BP.
PMID: 20606363 [PubMed - indexed for MEDLINE]
Graft-versus-host driven graft-versus-leukemia effect of minor histocompatibility antigen HA-1 in chronic myeloid leukemia patients.
Leukemia. 2010 Jul;24(7):1388-92
Authors: Mutis T, Brand R, Gallardo D, van Biezen A, Niederwieser D, Goulmy E, ,
PMID: 20508613 [PubMed - indexed for MEDLINE]
Hypopigmentation of the skin due to imatinib mesylate in patients with chronic myeloid leukemia.
Hematol Oncol Stem Cell Ther. 2009;2(2):358-61
Authors: Aleem A
BACKGROUND: Hypopigmentation is an infrequently reported adverse effect of imatinib mesylate (IM) in chronic myeloid leukemia (CML), but there are no reports from Arab or Saudi patients. Thus, we assessed the frequency and impact of hypopigmentation in patients with chronic myeloid leukemia (CML) taking IM in our institution in Riyadh. PATIENTS AND METHODS: We studied 24 adult CML patients taking IM and followed from March to June 2008. Telephonic interviews with all the CML patients taking IM were conducted and case notes were reviewed. Findings were confirmed on a subsequent clinic visit by a physician. Demographic features, disease status, response to IM, presence and severity of skin changes and impact of these changes on the patients and the disease were noted. RESULTS: Eight (33%) patients (6 males, 2 females) developed hypopigmentation due to IM. All patients had newly diagnosed, chronic phase CML and received 400 mg IM daily. The median age of the affected group was 37 years (range 18-54 years). Hypopigmentation developed during the first 3 months of treatment in 5 patients and 6 months or later in 3 patients. It was generalized in 7 patients and involved the hands and face in one patient. No photosensitivity was reported and none had other significant side effects. CONCLUSION: Hypopigmentation of the skin can develop in about one third of CML patients taking IM. Physicians taking care of CML patients should be aware of this and patients need to be warned before commencing IM, particularly in dark-skinned patients.
PMID: 20118061 [PubMed - indexed for MEDLINE]
Cepheid announced an exclusive collaboration with Novartis for the commercialization of a test for monitoring the BCR-ABL gene transcript in peripheral blood specimens from patients diagnosed with Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML). Together with other lab tests, monitoring levels of BCR-ABL transcripts in Ph+ CML patients will aid in patient management… (Source: Health News from Medical News Today)