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Michael J Mauro

Publications and source records attributed to Michael J Mauro.

15 recordsLinked to original sources
PubMed2006

BCR-ABL mRNA levels at and after the time of a complete cytogenetic response (CCR) predict the duration of CCR in imatinib mesylate-treated patients with CML.

Although most patients with chronic myeloid leukemia (CML) treated with imatinib mesylate achieve a complete cytogenetic response (CCR), some patients will relapse. To determine the potential of real-time quantitative BCR-ABL reverse transcriptase-polymerase chain reaction (RT-PCR) to predict the duration of continued CCR, we monitored 85 patients treated with imatinib mesylate who achieved a CCR. With a median follow-up of 13 months after CCR (29 months after imatinib mesylate; median 6 RQ-PCR assays), 23 patients (27%) had disease progression (predominantly loss of CCR). Compared with the median baseline level of BCR-ABL mRNA, 42% of patients achieved at least a 2-log molecular response at the time of first reaching CCR. Failure to achieve a 2-log response at the time of CCR was an independent predictive marker of subsequent progression-free survival (hazard ratio = 5.8; 95% CI, 1.7-20; P = .005). After CCR, BCR-ABL mRNA levels progressively declined for at least the next 15 months, and 42 patients (49%) ultimately achieved at least a 3-log reduction in BCR-ABL mRNA. Patients failing to achieve this 3-log response, at any time during therapy, had significantly shorter progression-free survival (hazard ratio = 8.1; 95% CI, 3.1-22; P < .001). The achievement of either a 2-log molecular response at the time of CCR or a 3-log response anytime thereafter is a significant and independent prognostic marker of subsequent progression-free survival.

Adult↗
PubMed2006

Defining and managing imatinib resistance.

While imatinib is highly effective therapy, with improving prospects over time for sustained remission and potential to severely limit or eliminate disease progression and transformation, a minority of patients either fail or respond suboptimally to imatinib; as well, disease eradication may not be possible with imatinib. Distinct patterns of resistance have evolved with the use of imatinib, and Abl kinase mutations, which alter imatinib binding or favor kinase conformations inaccessible to imatinib, are a common finding associated with clinical resistance. Dasatinib and nilotinib, alternate Abl kinase inhibitors, restore hematologic and cytogenetic remission in the majority of patients with primary failure or acquired resistance in chronic phase disease; in advanced disease and Philadelphia chromosome (Ph)(+) ALL, responses are more limited and relapse is common. Future studies with these agents will focus on further optimizing imatinib response, reduction of minimal residual disease, and prevention of resistance. Still newer inhibitors active against T315I mutant BCR-ABL may overcome primary and secondary resistance to dasatinib and nilotinib.

Benzamides↗
PubMed2006

Stem cell transplantation in patients with chronic myelogenous leukemia: when should it be used?

Hematopoietic stem cell transplantation has been a cornerstone of therapy for chronic myelogenous leukemia (CML) for more than 15 years and is still a standard treatment option for patients with CML. The advent of imatinib mesylate, an inhibitor of the molecular defect driving CML, the BCR-ABL tyrosine kinase, has rewritten treatment algorithms for this disease and has shifted focus away from allografting. Despite advances in stem cell transplantation, such as broader availability with the use of modified conditioning regimens, use of allografting has diminished. Also, the nearly universal patient exposure to imatinib or other kinase inhibitors before transplantation may affect the biology of the disease that is currently being treated with an allograft and ultimately may affect outcomes. Exceedingly high rates of meaningful and stable response with longer follow-up continue to drive enthusiasm for imatinib use, and understanding of resistance mechanisms has driven rapid investigation of second-generation tyrosine kinase inhibitors to address imatinib failure and suboptimal response. In most patients, imatinib reduces CML to a minimal residual disease state in which options to further deepen remission, such as immunotherapy, are sought; monitoring techniques and interpretation of response advance in parallel to meet demands; and uncertainty remains as a new natural history of CML is defined in an era of kinase inhibitor therapy. This review summarizes the state of transplant and nontransplant therapy for CML and discusses the decision making for patients with an aim to optimize the use of our best therapies for CML in an era of uncertainty.

Antineoplastic Agents↗
PubMed2005

Chronic myeloid leukemia: current application of cytogenetics and molecular testing for diagnosis and treatment.

Chronic myeloid leukemia provides an illustrative disease model for both molecular pathogenesis of cancer and rational drug therapy. Chronic myeloid leukemia is a clonal stem cell disease caused by an acquired somatic mutation that fuses, through chromosomal translocation, the abl and bcr genes on chromosomes 9 and 22, respectively. The bcr/abl gene product is an oncogenic protein that localizes to the cytoskeleton and displays an up-regulated tyrosine kinase activity that leads to the recruitment of downstream effectors of cell proliferation and cell survival and consequently cell transformation. Such molecular information on pathogenesis has facilitated accurate diagnosis, the development of pathogenesis-targeted drug therapy, and most recently the application of molecular techniques for monitoring minimal residual disease after successful therapy. These issues are discussed within the context of clinical practice.

Antimetabolites, Antineoplastic↗
PubMed2004

Divergent clinical outcome in two CML patients who discontinued imatinib therapy after achieving a molecular remission.

Imatinib mesylate therapy leads to major or complete cytogenetic response in the majority of patients with CML in the chronic phase. A subset of these patients also achieves remission at a molecular level. It is not known if such patients will require continuous therapy, or whether imatinib could be safely discontinued. This report describes divergent clinical outcomes in two patients with chronic phase CML who discontinued imatinib therapy after obtaining a molecular remission; one patient who maintained a complete molecular response throughout a period of interruption, and a second patient with overt relapse, highlighting the uncertainty of discontinuing imatinib therapy.

Adult↗
PubMed2003

Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate.

We followed 141 patients treated with imatinib mesylate (> 300 mg) for chronicphase chronic myelogenous leukemia (CML) following failure of treatment with interferon. During 12 months from the start of imatinib mesylate treatment, 96.5% achieved a complete hematologic response, 47.0% achieved a major cytogenetic response, and 32.4% achieved a complete cytogenetic response. The proportion of patients with hematologic relapse was 10.9% at 12 months and 14.6% at 18 months. In a univariate Cox regression analysis, the only pretreatment characteristics that correlated with an increased risk of hematologic relapse were hemoglobin level less than 120 g/L (12 g/dL) (P =.02), increased bands in the peripheral blood (P =.01), and clonal evolution (P <.0001). In a multivariate analysis, an elevated platelet count (P =.03) and clonal evolution (P <.0001) were the only significant factors for hematologic relapse. During treatment, the absence of a major cytogenetic response within the first 6 months also significantly correlated with relapse (P =.03). Notably, patients failing to achieve a major cytogenetic response by 6 months had a significantly higher rate of hematologic relapse (27%) compared with those who achieved a major cytogenetic response by 6 months (3%), and patients with clonal evolution had a significantly higher risk of hematologic relapse (50%) than those without clonal evolution (9%).

Adult↗
PubMed2003

Transplantation for chronic myelogenous leukemia: yes, no, maybe so. . . An Oregon perspective.

Chronic myelogenous leukemia (CML) is a hematopoietic stem cell disorder in which allogeneic stem cell transplantation remains the only curative option, but its use is limited by donor availability and treatment-related morbidity and mortality. Imatinib mesylate is a targeted agent for CML with efficacy to date, which is superior to all other nontransplant therapy and has limited toxicity. The curative potential of imatinib remains to be proven and may be limited to a small number of patients. Optimal decision making regarding the use of these divergent therapies has not been defined. This paper reviews critical data relevant to these treatment options and provides an approach to current management of the CML patient.

Algorithms↗
PubMed2003

STI571 as a targeted therapy for CML.

Chronic myelogenous leukemia (CML) is a clonal hematopoietic stem cell disorder that progresses through distinct phases as the malignant clone progressively loses the capacity for terminal differentiation. It is characterized by the (9;22) translocation and resultant production of the Bcr-Abl tyrosine kinase. Bcr-Abl functions as a constitutively activated tyrosine kinase, and this kinase activity is absolutely required for the transforming function of the Bcr-Abl protein. In preclinical studies, STI571 (Gleevec, imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor, specifically inhibited the proliferation of Bcr-Abl-expressing cells in vitro and in vivo. STI571 has shown remarkable results in all phases of CML. Although responses are seen in all phases of the disease, durable responses are most common in earlier stage patients. Thus, STI571 has emerged as a paradigm for gene product targeted therapy, offering expanded treatment options for patients with CML.

Antineoplastic Agents↗
PubMed2002

The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML.

In chronic myelogenous leukemia (CML), the development of chromosomal abnormalities in addition to the Philadelphia chromosome (clonal evolution) is considered by many to be a feature of accelerated phase (AP). Imatinib mesylate (STI571), a selective inhibitor of the Bcr-Abl tyrosine kinase, has significant activity in AP CML. As clonal evolution could allow Bcr-Abl independent proliferation, we analyzed its impact on the outcome of 71 AP patients treated with 600 mg of imatinib mesylate. Fifteen patients had clonal evolution alone (AP-CE), 32 had AP features but no evidence of clonal evolution (HEM-AP), and 24 had AP features plus clonal evolution (HEM-AP + CE). Of the AP-CE patients, 73% had a major cytogenetic response, compared with 31% of the HEM-AP patients (P =.043) and 12.5% of the HEM-AP + CE patients (P =.007). Complete cytogenetic responses were seen in 60% of AP-CE patients, compared with 31% of HEM-AP patients (P =.19) and 8% of HEM-AP + CE patients (P <.001). With mean follow-up of 11.2 months, 35% of all patients failed treatment. The lowest estimated rate of treatment failure at 1 year, 0%, was seen in AP-CE patients, compared with rates of 31% for HEM-AP patients and 69% for HEM-AP + CE patients (P =.0004). After 1 year, 100% of AP-CE patients were still alive, compared with 85% of HEM-AP patients and 67.5% of HEM-AP + CE patients (P =.01). In conclusion, in patients with clonal evolution as the sole criterion of disease acceleration, good responses to imatinib are still possible. Once patients have other signs of acceleration, clonal evolution predicts lower response rates and a shorter time to treatment failure.

Adult↗
PubMed2002

Hematopathologic and cytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients: 14 months' experience.

Imatinib mesylate, an Abl kinase inhibitor, produces sustained complete hematologic responses (CHRs) in chronic myelogenous leukemia (CML) patients, but the sequence and timing of morphologic and cytogenetic changes in CML patients during prolonged imatinib mesylate treatment has not been described. In this report, we document sequential hematologic and bone marrow findings in 19 interferon-refractory/interferon-intolerant chronic phase CML patients on imatinib mesylate for at least 14 months. Patients treated at an effective oral dose (300 to 600 mg per day) were followed with peripheral blood (PB) counts, marrow examination, and cytogenetic studies at 0, 2, 5, 8, 11, and 14 months. By 2 months, 17 of 19 patients achieved CHR; 1 reached CHR by 5 months, and 1 at 11 months. Five of 19 patients developed cytopenias requiring treatment interruption and/or dose reduction, but all were able to continue in CHR on study. In contrast to interferon-alfa treatment, imatinib mesylate-treated CML patients achieved not only CHR but complete morphologic marrow response. Normalization of marrow lagged behind PB response; however, by 8 months, all marrows showed normal or reduced cellularity without morphologic evidence of CML. Eighteen of 19 patients continued in CHR and morphologic marrow remission at 14 months; 1 patient relapsed with chronic phase CML. Although hematologic and marrow responses were uniform, cytogenetic responses were variable. Complete cytogenetic responses occurred in 6 patients, with 4 also in remission by fluorescent in situ hybridization and/or reverse-transcription-polymerase chain reaction. Six of 19 had partial and 7 of 19 no cytogenetic response. Several patients acquired additional clonal cytogenetic abnormalities during therapy, a finding with significant implications for prognosis and laboratory monitoring in imatinib mesylate-treated CML patients.

Adult↗
PubMed2002

STI571: a paradigm of new agents for cancer therapeutics.

STI571 exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. This article reviews the identification of Bcr-Abl as a therapeutic target in chronic myelogenous leukemia and the steps in the development of an agent to specifically inactivate this abnormality. Issues related to clinical trials of molecularly targeted agents are discussed, including dose selection, optimizing therapy, and predicting response, as are possible mechanisms of resistance to STI571. Lastly, the potential use of STI571 in other malignancies and the translation of this paradigm to other malignancies are explored.

Animals↗
PubMed2002

Recent advancements in the treatment of chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is a clonal hematopoetic stem cell disorder characterized by the Philadelphia chromosome and resultant production of the constitutively activated Bcr-Abl tyrosine kinase. Characterized clinically by marked myeloid proliferation, it invariably terminates in an acute leukemia. Conventional therapeutic options include interferon-based regimens and stem cell transplantation, with stem cell transplantation being the only curative therapy. Through rational drug development, STI571, a Bcr-Abl tyrosine kinase inhibitor, has emerged as a paradigm for gene product targeted therapy, offering new hope for expanded treatment options for patients with CML.

Antineoplastic Agents↗