WELCOME�TO �Journal Presentation

Department of Haematology

BSMMU

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Presented by

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Dr. Mehnaj Ashraf

Resident (Phase B)

Dept. of Haematology, BSMMU

�CNS involvement in AML at diagnosis is rare and does not affect response or survival: data from 11 ECOG-ACRIN trials�

Author: Chezi Ganzel et al

Published: November 23, 2021

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Introduction�

• Extramedullary disease (EMD) is a known manifestation of acute myeloid leukemia (AML) with an overall reported incidence ranging between 2.5% and 30%. Its rate is highest among patients with monocytic AML.
• Data regarding central nervous system (CNS) involvement in patients with newly diagnosed AML are

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scarce, and the prognostic implication of CNS involvement is controversial. There is also no current agreement regarding whether lumbar puncture (LP) should routinely be performed in every patient with newly diagnosed AML, similar to that performed in patients with acute lymphoblastic leukemia or in pediatric patients with AML.

Study Aim:

In this retrospective study, a very large database of 11 consecutive clinical trials of patients with newly diagnosed AML was reviewed.

The focus was on 3 issues:

• first, whether the incidence of CNS involvement at diagnosis was higher among the 5 studies in which an

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LP was mandatory for all patients (n=1753) than in studies in which patients received an LP only if neurologic symptoms were present and/or at the discretion of the physician (n=1487).

• The second issue was to describe the characteristics of patients with CNS involvement compared with

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patients without any EMD or with EMD other than in the CNS.

• The third issue was to report the prognosis of patients with CNS involvement compared with that of patients with other or no EMD.

Materials and Methods

Study design

• Study type: retrospective study
• Clinical trials led by ECOG-ACRIN
• Patients age 15 years or older with untreated AML were enrolled.
• Study Period: 1980 to 2008
• Sample size: Total 3420 enrolled patients

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EMD Assessment�

• In all 11 trials, bone marrow (BM) leukemic involvement was an eligibility criterion, meaning that patients with an isolated extramedullary myeloid sarcoma, including isolated CNS leukemia, without BM involvement were not included. The presence of EMD at baseline was defined clinically by physical examination and radiology without necessarily requiring a biopsy.

Statistical analysis�

• Descriptive statistics were used for patient demographics and disease characteristics.
• Wilcoxon 2-sample tests (for continuous variables) and Fisher’s exact tests (for categorical variables) were used to explore potential differences between groups.

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• The Kaplan-Meier method was used to estimate median overall survival (OS).
• Univariable and multivariable Cox proportional hazard models were used to evaluate the effect of CNS involvement on OS.
• A 2-sided P value of .05 was considered statistically significant.

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Results�

• Incidence of CNS involvement

Of the 3240 patients included in this analysis, 36 patients had CNS involvement (CNS-positive) at the time of diagnosis. The overall incidence was 1.11%, but it varied among the different studies (from 0% to 4.2%).

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The incidence of CNS disease among all patients in the 5 studies that mandated an LP was similar to the incidence among all patients in trials in which LP was performed solely on the basis of neurologic symptoms and/or at the discretion of the attending physician (0.86% vs 1.41%).

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• Characteristics of patients with CNS involvement

Half of the CNS-positive patients were males, the median age was 44.5 years (range, 17-79 years), 38.9% had an ECOG performance status of 2 or higher, and 55.6% had FAB (French-American-British classification of AML for acute myelomonocytic leukemia)-M4 disease.

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• Among the 39 patients, cytogenetic analysis was available in only 9 (which included 5 patients with normal karyotype and 1 patient each with t(8;21)(q22;q22) with –Y, t(6;9)(p23;q34), del (16)(q22), or 12mar with –Y).

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The rate of ECOG PS 2 to 4 was highest among CNS-positive patients (38.9%), intermediate among patients with other EMD sites (22.9%), and lowest among patients without EMD (14%).

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• Compared with patients without EMD, CNS-positive patients were younger (median age. 44.5 vs 52 years; P=.07) and had a higher median WBC count (P= .0004).

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Response and survival by CNS involvement:

• The rate of complete remission (CR) among CNS-positive patients was similar to that in the other groups (52.8% vs 59.3%-60%; P=.49).
• The median OS was 11.4 months (95% confidence

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interval [CI], 7.2-17.7 months) among CNS-positive patients, 11.3 months (95% CI, 10.4-12.8 months) among patients with other EMD, and 12.7 months (95% CI, 12.1-13.7 months) among those without EMD.

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• The hazard ratios (HRs) for OS of CNS-positive patients compared with the other EMD patients was 1.07 (95% CI, 0.75-1.53; P 5 .70) and 1.22 (95% CI, 0.86-1.74) compared with patients without EMD (P=.26).

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• Among the 36 patients who were CNS-positive, there was no significant difference in the CR rate between patients with other EMD (n=23) and those with CNS only (n=13) (60.9% vs 38.5%; P=.30).
• Similarly, no significant difference in OS was observed between the CNS-positive patients with

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other EMD and the CNS only groups (HR for other EMD vs CNS only, 1.95; 95% CI, 0.89-4.30; P=.10). The same conclusion remains using multivariable analysis (P=.26).

Discussion�

• CNS involvement in adults with newly diagnosed AML is a rare phenomenon with limited published data.
• The need for and clinical impact of a routine LP have remained unclear.
• Among pediatric patients, CNS assessment is part of the routine evaluation but the prognostic impact of CNS involvement remains controversial.

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• This study examined a very large database of 11 ECOG-ACRIN consecutive clinical trials that had a total of 3240 patients with newly diagnosed AML to gain more information about this phenomenon, focusing on the relationship between CNS involvement and other sites of EMD, its incidence with or without a routine LP, and its overall prognostic impact.

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• The incidence of CNS involvement at diagnosis was 1.1%, similar to the 0.9% that was published relatively recently.
• The rate of FAB-M4 disease, incidence of ECOG PS 2 to 4, and median level of initial WBC count were highest in CNS-positive patients, intermediate in patients with EMD other than CNS, and lowest in patients without EMD.

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• Almost two-thirds of CNS-positive patients also had other sites of EMD, which supports the assumption that the ability of the disease to involve extramedullary sites is an intrinsic character of the specific leukemic phenotype, possibly related to expression of surface adhesion molecules.

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• An intriguing issue regarding CNS involvement in AML is whether routine performance of an LP in every patient with AML, regardless of symptoms, will increase the rate of detection.
• This study data suggest that a routine LP does not increase the detectable rate of CNS involvement.

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• Importantly, patients who are CNS positive do not have a worse OS compared with other patients who have EMD or those without EMD.
• In this study, other than the initial therapy at diagnosis (for example, adding IT MTX according to each protocol), the protocols did not permit for any significant deviations, such as administering more intensive therapy to patients with CNS involvement.

Limitations

• It was a retrospective analysis that examined clinical trials that spanned 3 decades.
• Data about CNS imaging studies and BM cytogenetics are clearly limited, and FC was not part of the CSF assessment.
• Although few patients had CNS involvement in each of the 11 studies, the consistent pattern in this very large cohort of 3500 patients lends credence to the overall analysis and conclusions.

Conclusion

• This retrospective analysis reported a low incidence of CNS involvement in patients with newly diagnosed AML and does not encourage routinely performing an LP.
• Assuming that prompt CNS-directed therapy is given, their data do not support a prognostic characterization or a recommendation for using a different systemic chemotherapy.

Acknowledgments:

• This study was supported by grants from the National Institutes of Health, National Cancer Institute and was coordinated by Peter J. O’Dwyer, and Mitchell D. Schnall, Group Co-Chairs of the ECOG-ACRIN Cancer Research Group.

Thank You�Eid Mubarok