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M J Keating

Publications and source records attributed to M J Keating.

At least 181 records · Page 10Linked to original sources

New initiatives with fludarabine monophosphate in hematologic malignancies.

Fludarabine monophosphate (fludarabine) was initially discovered to have significant activity in indolent lymphoma and chronic lymphocytic leukemia (CLL). The major clinical experience with fludarabine is in previously treated patients with CLL. In such patients the complete and partial response rate (CR + PR) is over 50%. These results were obtained with 5-day schedules of fludarabine 25 to 30 mg/m2/d. Subsequent schedules have explored once-a-week fludarabine and a 3-day schedule every 4 weeks. These strategies, in particular the once-a-week schedule, have obtained inferior results. The addition of prednisone has not been associated with an improvement in response rate or survival. The application of fludarabine to previously untreated patients demonstrated a CR + PR rate of 75% to 80%. The addition of prednisone did not improve the response rate or survival in this group of patients. A significant concern in patients with CLL treated with fludarabine is a decrease in the CD4 and CD8 counts. Despite median posttreatment counts of approximately 200 CD4 lymphocytes/microL, the incidence of infections in patients in remission off therapy is low. Major clinical activity has been demonstrated with fludarabine in Waldenstrom's macroglobulinemia, in which more than one third of refractory patients achieve a CR or PR. Responding patients with anemia or thrombocytopenia have a marked improvement in blood counts. The duration of response has been long (> 30 months) in most responders. The early activity of fludarabine as a single agent in phase I/II studies in indolent lymphoma subsequently has been confirmed by a number of investigators. Fifty percent to 60% of patients with follicular lymphomas respond to fludarabine as a single agent. A number of these responses are complete despite the patients having received extensive prior treatment. A number of combination programs are being developed in CLL and indolent lymphoma. The combination of fludarabine with doxorubicin and prednisone has been developed and is being studied in phase I/II clinical trials. In addition, combinations of fludarabine and cytarabine with or without cisplatin based on elegant preclinical pharmacokinetic rationales have been applied to CLL with impressive cytoreductive activity but significant myelosuppression. A new combination of fludarabine, mitoxantrone, and dexamethasone has been developed for use in lymphoma. Phase I studies demonstrated a high response rate, especially in follicular lymphomas, with a number of patients achieving complete remission. Subsequent phase II studies demonstrate a response rate of 89% in patients with indolent lymphoma.(ABSTRACT TRUNCATED AT 400 WORDS)

Antimetabolites, Antineoplastic↗

Fludarabine: pharmacokinetics, mechanisms of action, and rationales for combination therapies.

Knowledge of the pharmacokinetics of a drug is essential to the optimal design of the dose and schedule of chemotherapy protocols. As an extension, an understanding of the mechanism of drug action is necessary to construct the optimal strategy for combination chemotherapy. Nucleoside antimetabolites such as fludarabine are pro-drugs that must enter cells and be phosphorylated to the nucleoside triphosphate before they can elicit biologic activity. Thus, knowledge of the pharmacokinetics of the triphosphate in target cells and an understanding of the mechanisms by which this active form of the drug act are indispensable to the rational design of treatment protocols. This article reviews the essential elements of the pharmacokinetics and mechanisms of action of fludarabine to provide a rationale for combinations of fludarabine with other chemotherapeutic agents and anti-cancer modalities.

Antineoplastic Agents↗

Chronic lymphoproliferative disorders: chronic lymphocytic leukemia and hairy-cell leukemia.

A consistent stimulus to increase interest in malignant disease is the discovery of new successful treatments. The dramatic activity of the nucleoside analogues, 2'-deoxycoformycin, fludarabine, and 2-chlorodeoxyadenosine, in indolent lymphoproliferative diseases has caused a reawakening of interest in the biology and treatment of chronic lymphocytic leukemia and hairy-cell leukemia. The high response rate has led to a reevaluation of criteria for response in these diseases as well as indications for treatment and prognostic factors.

Humans↗

A topographic representation of auditory space in the external nucleus of the inferior colliculus of the guinea-pig.

The possibility that the external nucleus of the inferior colliculus (ICX) of the pigmented guinea-pig contains a map of auditory space has been investigated. Auditory stimuli consisted of broad-band sound delivered under free-field anechoic conditions from a range of positions around the animal's azimuthal axis. The responses of clusters of neurons in the ICX to threshold and to near-threshold stimuli displayed sharp spatial tuning. The responses recorded from rostral ICX revealed a preference for auditory stimuli in the anterior field while more caudal neurons preferentially responded to sounds presented in the posterior field. Neurons at intermediate points, along the rostro-caudal axis of the nucleus, displayed preferences for sound stimuli in appropriately intermediate field positions along the contralateral azimuthal axis. At higher stimulus intensities the spatial tuning of the responses decreased, but the optimal direction of preference was usually retained. The contribution of binaural processing to auditory spatial tuning was evident, since unilateral cochlea ablation destroyed the spatial tuning at higher stimulus intensities. The results presented provide the first evidence that a topographically ordered representation of the contralateral auditory azimuth is present in the ICX of a mammal.

Acoustic Stimulation↗

Response assessment in chronic lymphocytic leukemia after fludarabine plus prednisone: clinical, pathologic, immunophenotypic, and molecular analysis.

The goals of this study were to evaluate the response to treatment in chronic lymphocytic leukemia (CLL) according to clinical, pathologic, immunophenotypic, and molecular features, as well as to address the clinical significance of each finding. One hundred fifty-nine CLL patients with either advanced Rai stage III or IV (81 patients) or progressive Rai stage 0 to II (78 patients) were treated with fludarabine (30 mg/m2/d intravenously every day for 5 days) plus prednisone (30 mg/m2/d orally daily for 5 days). Thirty-six patients were previously untreated. The response rates were 12% complete response (CR), 30% nodular complete response (nCR), and 18% partial response (PR). In all patients who achieved a complete response (both CR and nCR) less than 30% of nucleated cells were lymphocytes on marrow aspirate differential analysis; however, nCR patients had residual nodular and/or interstitial lymphocyte involvement on marrow biopsy examination. There was no evidence of leukemic infiltration on marrow biopsy examination in CR patients. With a median follow-up of 35 months, comparison of time to progression in the CR and nCR groups at 2 years showed a projected 87% versus 55% progression-free survival (P less than .03). Residual disease assessment by flow cytometry using simultaneous dual-color staining on blood and marrow lymphocytes was also performed on each patient. Residual disease was determined by the expression of CD5 on B lymphocytes and the monoclonality of surface light-chain expression. After six courses of fludarabine plus prednisone, no residual disease was detected by flow cytometry in 89% of the CRs, 51% of the nCRs, and 19% of the PRs. Clinical residual disease in PR patients with no residual disease detectable by flow cytometry was limited to lymph-adenopathy. Time to progression at 2 years was longer in CR and nCR patients having no residual disease detected by flow cytometry (84% v 39% 2-year progression-free survival, P less than .001). Posttreatment lg gene rearrangement analysis using JH, J kappa, and C lambda probes demonstrated no rearranged bands and a return to the germline configuration in five of seven CRs and two of eight nCRs studied. The molecular studies were concordant with the dual-parameter immunophenotype results and none of the patients who reverted to a germline DNA pattern after treatment have experienced relapse. The absence of detectable minimal residual disease by bone marrow biopsy, dual-color flow cytometry, and lg gene rearrangement analysis is achieveable in CLL with fludarabine and is predictive of the response duration.

Adult↗

Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA).

We administered one course of 2-chlorodeoxyadenosine (2CdA) at 4 mg/m2 daily for 7 days by continuous intravenous infusion to 46 patients with hairy cell leukemia. Complete remissions occurred in 36 patients (78%; 95% confidence limits, 63% to 89%), partial remissions in five (11%), and a minor response in one. One patient died of candida sepsis 3 weeks after beginning treatment and three patients were clearly resistant to therapy. These three either had morphologically atypical hairy cells, less than 20% of which expressed Ig light chain on the cell surface, or had failed prior treatment with deoxycoformycin and interferon-alpha. At a median of 37 weeks since discontinuation of therapy, recurrent thrombocytopenia has developed in one patient, whose marrow remains normal, while a bone marrow relapse has occurred in another patient, whose blood counts remain normal. Treatment produced a greater than 50% decrease in neutrophil count in 26 patients, which lasted 3 to 4 weeks and was associated with an increased incidence of febrile episodes. These episodes occurred in 21 patients but were associated with documented infection in only four patients. Decreases in the number of CD4+ lymphocytes appeared to occur regularly after treatment and have persisted for a median of 18 weeks without obvious clinical significance. Although years of follow-up will be needed, our results confirm Piro et al's observation (N Engl J Med 322: 1117, 1990) that 2CdA appears to be highly effective in the treatment of hairy cell leukemia.

2-Chloroadenosine↗

Intensive chemotherapy with mitoxantrone and high-dose cytosine arabinoside followed by granulocyte-macrophage colony-stimulating factor in the treatment of patients with acute lymphocytic leukemia.

Thirty-four adults with refractory acute lymphocytic leukemia received salvage therapy with mitoxantrone 5 mg/m2 intravenously over 1 hour daily for 5 days and cytosine arabinoside (ara-C) 3 g/m2 intravenously over 2 hours every 12 hours for six doses, followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) 125 microgram/m2 intravenously over 4 hours daily until recovery of granulocytes above 2.0 x 10(3)/microL. Their outcome was compared with 29 prognostically similar historical control patients treated with the identical chemotherapy without GM-CSF. Overall, the complete response rates were similar in the treatment and control groups (13 of 34 [38%] v 11 of 29 [38%]). There was a trend for less remission induction mortality in the GM-CSF-treated patients (2 of 34 [6%] v 6 of 29 [21%]; P = .08), but, conversely, a higher rate of resistant disease (19 of 34 [56%] v 10 of 29 [34%]; P = .09). Recovery of granulocyte counts above 500/microL was significantly faster in the GM-CSF-treated group (25 days v 33 days; P less than .01), but there was no reduction in the incidence of febrile episodes (91% v 93%) or of documented infections (59% v 59%). Survival was prolonged in the GM-CSF-treated patients but was not of clinical relevance (31 v 20 weeks; P = .05). In summary, the addition of GM-CSF to intensive chemotherapy in refractory adult ALL was associated with a reduction in the remission induction mortality, probably secondary to a shorter duration of granulocytopenia, but not with an improvement in complete response rates.

Adult↗

Fludarabine infusion potentiates arabinosylcytosine metabolism in lymphocytes of patients with chronic lymphocytic leukemia.

Our previous work has shown that incubation of K562 cells or lymphocytes from patients with advanced chronic lymphocytic leukemia (CLL) with arabinosyl-2-fluoroadenine (F-ara-A) potentiates the rate of arabinosylcytosine 5'-triphosphate (ara-CTP) synthesis during subsequent treatment with arabinosylcytosine (ara-C). To test the biochemical modulation of ara-CTP in a clinical setting, we designed a protocol to administer fludarabine (Fludara, F-ara-AMP) and ara-C in a pharmacologically directed sequence for patients with CLL refractory to conventional fludarabine therapy. ara-C was infused in seven patients with progressive CLL at a dose rate that maximizes ara-CTP accumulation (0.5 g/m2 during 2 h). Fludarabine (30 mg/m2 during 30 min) was infused 20 h later, followed by a second, identical dose of ara-C at 24 h, when the concentration of F-ara-A 5'-triphosphate (F-ara-ATP) was maximal in CLL cells. Comparison of ara-CTP pharmacokinetics in circulating CLL cells demonstrated that the ara-CTP area under the curve increased by a median of 1.5-fold (range, 1.1- to 1.7-fold) after fludarabine infusion. Plasma pharmacokinetics indicated that neither the median steady-state ara-C concentrations nor the levels of its deamination product arabinosyluracil were significantly affected by fludarabine infusion. The median rate of ara-CTP elimination was slightly faster after fludarabine treatment (t1/2, 6.7 versus 5.8 h), suggesting that catabolism of ara-CTP was not responsible for the increased ara-CTP area under the curve. The rate of ara-CTP accumulation by CLL cells after fludarabine infusion, however, was increased by a median of 1.3-fold in seven of the eight patients (range, 1.2- to 1.8-fold); the peak occurred within 1 h of the end of the infusion. In vitro incubation of leukemic lymphocytes with F-ara-A before ara-C also showed a median 1.3-fold increase in the rate of ara-CTP accumulation. Thus, infusion of fludarabine before ara-C augments ara-CTP metabolism in leukemic lymphocytes. This knowledge should be considered in the design of combination chemotherapy.

Antineoplastic Agents↗

Changing patterns of binocular visual connections in the intertectal system during development of the frog, Xenopus laevis. III. Modifications following early eye rotation.

In the frog, Xenopus laevis, a system of intertectal connections underlies the visual projection from an eye to its ipsilateral tectal lobe and is involved in the topographic representation of binocular visual space. Rotation of one eye in early life may be followed by a radical rearrangement of the connections in this system. The modified pattern which later emerges is that which keeps the visual projection through the ipsilateral eye in topographic registration with the direct visual projection from the contralateral eye to the same tectal lobe. This plasticity requires visual experience. In this paper we describe the time-course and sequence of events by which this plasticity is effected. Following rotation of one eye in larval animals or in animals undergoing metamorphic climax, the earliest evidence of intertectal modification was found 3-4 weeks after metamorphosis. With increasing intervals after metamorphosis an increasing proportion of animals displayed modified intertectal systems. At intermediate intervals many animals showed partial modifications, which were interpreted as transitional stages in the modification process. Analysis of these transitional stages indicated that the sequence of events involved in the elaboration of a modified intertectal system following the experimental alteration of eye alignment exhibits features in common with rearrangements of the system that occur during normal development in response to growth-related alterations in eye alignment.

Animals↗

Plasticity of binocular visual connections in the frog, Xenopus laevis: reversibility of effects of early visual deprivation.

In frogs, each lobe of the midbrain optic tectum receives two spatially aligned maps of binocular visual space, one through each eye. The map from the contralateral eye is the product of direct retinal input to the tectum, while that from the ipsilateral eye is mediated by a commissural system of connections that relays binocular visual information from one tectal lobe to the other. In Xenopus laevis, dark-reared from early life, the visuotectal map through the ipsilateral eye exhibits significant signs of disorder indicating that the normal development of the underlying "intertectal" system involves experience-dependent processes. Here we investigate the potential of this system for recovery from such deprivation-induced disruption. Three groups of animals were first dark-reared from embryonic stages until 3 months, 12 months or 2 years after metamorphosis. These short-, medium- and long-term periods of visual deprivation are associated with a progressive disturbance of the intertectal system (Grant and Keating 1989b). The animals then experienced 12-18 months in a normal visual environment, before an electrophysiological mapping experiment was carried out to reveal the status of their intertectal system. Quantitative analyses of the visuotopic order in the ipsilateral visuotectal map and of its spatial alignment with the map derived from the contralateral eye revealed that these features were completely normal in all 3 experimental groups. It is concluded that defects present in the intertectal system of dark-reared Xenopus can be repaired by subsequent visual experience, and that the reparative capacity is not limited either by the animal's age or by the existing degree of prior disruption.

Animals↗

Prognostic significance of elevated serum beta 2-microglobulin levels in adult acute lymphocytic leukemia.

PURPOSE: Elevated serum beta-2 microglobulin (beta 2M) levels are associated with poor prognosis in several lymphoproliferative disorders including multiple myeloma and lymphoma. Their prognostic relevance in acute lymphocytic leukemia (ALL) is unknown. We analyzed the associations of serum beta 2M levels at diagnosis with pretreatment characteristics and with prognosis in adult ALL. PATIENTS AND METHODS: One hundred fifty-nine adults with newly diagnosed ALL were investigated. Serum beta 2M levels were determined at diagnosis, on fresh peripheral blood samples, using a radioimmunoassay, the Pharmacia beta 2 Micro RIA (Pharmacia Diagnostics, Uppsala, Sweden). Statistical correlations were assessed by standard methods, and further independent prognostic value of serum beta 2M was determined by multivariate analysis. RESULTS: Patients with beta 2M levels of 4.0 mg/L or above had a lower complete response rate (61% versus 80%; p = 0.02), a significantly worse survival (p < 0.01), and a significantly higher association with development of central nervous system (CNS) leukemia (p < 0.01). High beta 2M levels were more common among patients with older age, with elevated creatinine, bilirubin, and alkaline phosphatase levels, with low albumin levels, and with B-cell disease. Multivariate analysis for survival indicated the beta 2M level to be an independent prognostic variable (after adjusting for pretreatment creatinine level and age). The evaluation of beta 2M levels within low- and high-risk groups for CNS disease suggested an association of elevated beta 2M levels with a worse incidence of CNS disease in the high-risk patients. CONCLUSION: Monitoring serum beta 2M levels may provide significant prognostic information in adults with ALL and should be included in their pretreatment evaluation. Its importance in childhood ALL requires investigation.

Adult↗

Orofacial fungal infections. Nine pathogens that may invade during chemotherapy.

Immunosuppression due to antineoplastic drugs or malignant tumor leaves patients extremely vulnerable to infection. Opportunistic fungi that rarely infect healthy persons can have very severe consequences in these patients. Candida albicans is the pathogen found most often, but several other Candida species may cause infection as well. Aspergillosis is the second most frequently seen fungal infection of the face and mouth in patients receiving chemotherapy. Less commonly seen but equally dangerous are infections with Torulopsis glabrata, Mucor, Absidia, Rhizopus oryzae, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Fusarium species, and Trichosporon cutaneum. Restoration of impaired host defenses and use of nystatin (Mycostatin, Nilstat, O-V Statin), clotrimazole (Mycelex), amphotericin B (Fungizone Intravenous), and flucytosine (Ancobon) when appropriate are methods of control.

Antineoplastic Agents↗

Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, high-dose cytarabine, and granulocyte-macrophage colony-stimulating factor.

PURPOSE: The study was undertaken to improve the results of intensive chemotherapy in chronic myelogenous leukemia (CML) in accelerated (CML-AP) and blastic phases (CML-BP) by the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) as supportive therapy. PATIENTS AND METHODS: Forty-eight patients were treated with daunorubicin 120 mg/m2 intravenously on day 1, cytarabine (ara-C) 1.5 g/m2/d by continuous infusion over 24 hours for 4 days, and Solu-Medrol (methylprednisolone; The Upjohn Co, Kalamazoo, MI) 100 mg/d for 5 days, followed on day 5 by GM-CSF 125 micrograms/m2/d over 6 hours until recovery of granulocyte count above 2.0 x 10(3)/microliters. Twenty-four patients had CML-BP, and 24 had CML-AP. RESULTS: During remission induction, 45 patients (94%) developed febrile episodes (fever of unknown origin, 23 patients [48%]; documented infections, 22 patients [46%]). The median time to recovery of granulocyte count above 0.5 x 10(3)/microliters was 29 days and to platelet count above 30 x 10(3)/microliters, 28 days. Overall, 14 of 48 patients (29%) achieved a complete hematologic remission (CHR), and seven (15%) reverted to a second chronic phase. CHR was noted in eight of 24 patients with CML-BP (33%), and in six of 24 patients with CML-AP (25%). Cytogenetic responses were observed in 11 patients (23%), but were transient. Sixteen patients developed either fluid retention, hypotension, pleuropericardial effusions, or pericarditis, or a combination of these side effects. These side effects were severe in four patients and are likely to be disease-associated, as a similar regimen of intensive chemotherapy and GM-CSF at the same dose and schedule in acute lymphocytic leukemia was not associated with these side effects. CONCLUSIONS: The results pertinent to remission rates, induction mortality, myelosuppression profile and related complications, and overall survival were not significantly improved compared with previous experience. In summary, the results of intensive chemotherapy in CML-transformed phases remain poor, despite the addition of GM-CSF as a supportive measure.

Adult↗

Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-alpha and low-dose cytarabine.

PURPOSE: To evaluate the efficacy of interferon-alpha (IFN-A) and low-dose cytarabine (ara-C) combination chemotherapy in patients with chronic myelogenous leukemia (CML). PATIENTS AND METHODS: Sixty patients with advanced phases of Philadelphia chromosome (Ph)-positive CML received combination therapy with IFN-A 5 x 10(6) U/m2 daily, and low-dose ara-C 15 mg/m2 daily for 2 weeks every 4 weeks until remission, then for 1 week every month as maintenance. Forty patients were in late chronic-phase CML, and 20 were in accelerated-phase CML (16 with clonal evolution only, four with other criteria). Their outcome was compared with 58 patients (39 late chronic-phase CML and 19 accelerated-phase CML) who had been previously treated with IFN-A alone in the same dose schedule. RESULTS: In late chronic-phase CML, patients receiving IFN-A plus ara-C had a better complete hematologic response (CHR) rate compared with those treated with IFN-A alone (55% v 28%; P = .02), a trend for better Ph suppression (15% v 5%; P = .13), and a longer survival (3-year survival rate 75% v 48%; P less than .01). These differences do not seem to be caused by imbalances in prognostic factors between the two treatment groups. In accelerated-phase CML, the addition of ara-C to IFN-A did not improve the response rate of treated patients, and the difference in survival was accounted for by different patient characteristics. Suppression of clonal evolution was observed in five patients (25%). Patients with clonal evolution as the only criterion for disease acceleration had a longer survival than those with other or additional accelerated-phase criteria (3-year survival rate 67% v 22%; P less than .01). CONCLUSION: The results with the combination of IFN-A plus ara-C in late chronic-phase CML are encouraging, and suggest the need for its evaluation in early chronic-phase CML.

Adult↗

Phase II trial of fludarabine phosphate in lymphoma: an effective new agent in low-grade lymphoma.

PURPOSE: In a phase II trial we investigated fludarabine phosphate (FAMP) as therapy for patients with relapsed lymphoma to determine its effectiveness and toxicity in this disease. PATIENTS AND METHODS: The 67 assessable patients had a median age of 56 years and had received a median of three chemotherapy regimens before treatment with FAMP. The starting dose was 25 mg/m2 administered intravenously over 30 minutes daily for 5 days every 3 to 4 weeks. RESULTS: High response rates were observed for follicular small cleaved-cell lymphoma (FSCCL) (62%), follicular mixed small- and large-cell lymphoma (80%), and follicular large-cell lymphoma (FLCL) (100%). Responses also occurred in small lymphocytic lymphoma (SLL) (33%), transformed lymphoma (33%), mycosis fungoides (40%), and Hodgkin's disease (25%). No responses were observed in other intermediate- or high-grade lymphomas (N = 20). Overall, there were five patients with a complete response, 23 patients with a partial response, and an overall response rate of 37%. Toxicity was primarily hematologic and infectious. No significant gastrointestinal, hepatic, renal, or neurologic toxicity occurred. CONCLUSIONS: We conclude that FAMP has major activity in follicular lymphoma. Fundamental research is needed to understand this differential efficacy in low-grade lymphoma yet lack of efficacy in intermediate- and high-grade lymphoma. Clinical investigations should be done using FAMP in varying dose schedules and in combination regimens.

Adult↗

Cytogenetics for detection of minimal residual disease in acute myeloblastic leukemia.

Bone marrow samples collected from acute myeloblastic leukemia (AML) patients in complete clinical and hematological remission were studied for the persistence of cytogenetic abnormalities. AML patients from the three favorable cytogenetic categories [inv 16, t(8;21) and t(15;17)] and patients from the unfavorable cytogenetic categories (+8, -5, -7 and Philadelphia-positive) were studied. Seventy-one patients had evaluable metaphase spreads in remission marrows and 20 (28%) had one or more abnormal metaphases identical to that present in the pretreatment marrow. All 20 of these patients relapsed within 78 weeks, thus there were no false positive studies. Fifty-one patients had only diploid metaphases in their complete remission marrow, 25 relapsed, and 21 remained in continuous complete remission. Thus there was a 49% false negative rate of this study. These data indicate that the failure to detect residual chromosomally abnormal cells in the bone marrow does not guarantee continuous complete remission. Cytogenetic study was most useful in the favorable cytogenetic groups and least useful in the unfavorable groups. The persistence of normal metaphases in pretreatment marrows did not affect outcome or risk of recurrence. Twenty-five of 34 evaluable patients who relapsed after remission had either the identical cytogenetic abnormality present in the pretreatment marrow or showed the identical abnormality with additional chromosomal changes. Thus study indicates that cytogenetic examinations of complete remission bone marrow samples in patients with AML provides an objective method for detecting residual leukemia, and identifies patients with a potential for prolonged disease-free survival.

Bone Marrow↗