Prognostic factors associated with leukemia characteristics

WBC count: WBC count at diagnosis has been consistently noted to be inversely related to survival.[11,31,49,50] Patients with high presenting leukocyte counts have a higher risk of developing pulmonary and CNS complications and, historically, have a higher risk of death during induction.[51]

FAB subtype: Associations between FAB non-M3 subtypes and prognosis have been more variable.

FAB subtype: Associations between FAB non-M3 subtypes and prognosis have been more variable.

M0 subtype. The M0, or minimally differentiated subtype, has been associated with a poor outcome.[52]

FAB subtype: Associations between FAB non-M3 subtypes and prognosis have been more variable.

M6 subtype. In the 2016 WHO classification system, the M6 subtype was limited to pure erythroid leukemia. The combined COG AAML0531 and AAML1031 studies demonstrated that it is a rare subtype (5 of 1,934 cases; 0.2%), occurs in younger patients (median age, 2.3 years), and is associated with a poor outcome (5-year EFS and OS rates, 20% ± 36%).[53]

FAB subtype: Associations between FAB non-M3 subtypes and prognosis have been more variable.

M7 subtype. Some studies have indicated a relatively poor outcome for M7 (megakaryocytic leukemia) in patients without Down syndrome,[40] although reports suggest an intermediate prognosis for this group of patients when contemporary treatment approaches are used.[10,54,55]In a retrospective study of non–Down syndrome M7 patients with samples available for molecular analysis, the presence of specific genetic abnormalities (CBFA2T3::GLIS2 [cryptic inv(16)(p13q24)], NUP98::KDM5A, t(11;12)(p15;p13), KMT2A [MLL] rearrangements, monosomy 7) was associated with a significantly worse outcome than for other M7 patients.[56,57] By contrast, the 10% of patients with AMKL and GATA1 variants without Down syndrome appeared to have a favorable outcome if there were no prognostically unfavorable fusion genes also present, as did patients with HOX rearrangement.[57]

CNS disease: CNS involvement at diagnosis is categorized on the basis of the presence or absence of blasts in cerebrospinal fluid (CSF). European cooperative groups have applied ALL definitions of various degrees of CNS involvement to AML, as follows:

CNS disease: CNS involvement at diagnosis is categorized on the basis of the presence or absence of blasts in cerebrospinal fluid (CSF). European cooperative groups have applied ALL definitions of various degrees of CNS involvement to AML, as follows:

CNS1: CSF negative for blasts on cytospin, regardless of CSF WBC count.

CNS disease: CNS involvement at diagnosis is categorized on the basis of the presence or absence of blasts in cerebrospinal fluid (CSF). European cooperative groups have applied ALL definitions of various degrees of CNS involvement to AML, as follows:

CNS2 is divided into the following three subgroups, which are defined as follows:

CNS disease: CNS involvement at diagnosis is categorized on the basis of the presence or absence of blasts in cerebrospinal fluid (CSF). European cooperative groups have applied ALL definitions of various degrees of CNS involvement to AML, as follows: › CNS2 is divided into the following three subgroups, which are defined as follows:

CNS2a: CSF with fewer than 5 WBC/μL and cytospin positive for blasts in an atraumatic tap (<10 red blood cells [RBC]/μL).

CNS disease: CNS involvement at diagnosis is categorized on the basis of the presence or absence of blasts in cerebrospinal fluid (CSF). European cooperative groups have applied ALL definitions of various degrees of CNS involvement to AML, as follows: › CNS2 is divided into the following three subgroups, which are defined as follows:

CNS2b: CSF with fewer than 5 WBC/μL and cytospin positive for blasts in a traumatic tap (≥10 RBC/μL).

CNS disease: CNS involvement at diagnosis is categorized on the basis of the presence or absence of blasts in cerebrospinal fluid (CSF). European cooperative groups have applied ALL definitions of various degrees of CNS involvement to AML, as follows: › CNS2 is divided into the following three subgroups, which are defined as follows:

CNS2c: CSF with 5 or more WBC/μL and cytospin positive for blasts in a traumatic tap (≥10 RBC/μL) in which the WBC/RBC ratio in the CSF is less than twice that in the peripheral blood.

CNS disease: CNS involvement at diagnosis is categorized on the basis of the presence or absence of blasts in cerebrospinal fluid (CSF). European cooperative groups have applied ALL definitions of various degrees of CNS involvement to AML, as follows:

CNS3 includes the following three subgroups, which are defined as follows:COG trials (including AAML03P1 [NCT00070174], AAML0531 [NCT00372593], and AAML1031 [NCT01371981]) used a modified version of the CNS disease definitions, in which patients were dichotomously classified for treatment purposes as CNS positive or negative. The CNS-positive group included all patients with blasts on cytospin (regardless of CSF WBC) unless there were more than 100 RBC/μL in the CSF. Patients with 100 RBC/μL in the CSF were CNS positive only if the WBC/RBC ratio in the CSF was greater than or equal to twice the ratio in the peripheral blood. CNS outcomes on COG studies were analyzed using the more traditional CNS1/2/3 definitions.[58]In children with AML, CNS2 disease has been observed in approximately 13% to 16% of cases, and CNS3 disease has been observed in approximately 11% to 17% of cases.[58,59] Studies have variably shown that patients with CNS2/CNS3 disease were younger, more often had hyperleukocytosis, and had higher incidences of t(9;11), t(8;21), or inv(16).[58,59]While CNS involvement (CNS2 or CNS3) at diagnosis has not been shown to be correlated with OS in most studies, a COG analysis of children with AML enrolled from 2003 to 2010 on two consecutive and identical backbone trials found that CNS disease was associated with inferior outcomes, including decreased CR rate, EFS, and disease-free survival (DFS), and an increased risk of relapse involving the CNS.[58] Another trial showed it to be associated with an increased risk of isolated CNS relapse.[60] The COG study did not find traumatic lumbar punctures at diagnosis to have an adverse impact on OS.[58] From an analysis of patients enrolled in the AAML0531 and AAML1031 trials, using the COG definition of CNS involvement, peripheral blood contamination increased the number of patients who were classified as CNS positive and guided to additional intrathecal therapy.[61] In these trials, following past precedence, diagnostic CSF examinations and initial intrathecal administration were done on or before day 1 of induction therapy. Beginning with the COG AAML1831 (NCT04293562) trial, to minimize the contamination risk, the newer guidance is to delay the diagnostic lumbar puncture to day 8, when most patients have cleared their peripheral blood of leukemic blasts. Additionally, a definition of CNS involvement that is more similar to the ALL definition is now in use.

CNS disease: CNS involvement at diagnosis is categorized on the basis of the presence or absence of blasts in cerebrospinal fluid (CSF). European cooperative groups have applied ALL definitions of various degrees of CNS involvement to AML, as follows: › CNS3 includes the following three subgroups, which are defined as follows:COG trials (including AAML03P1 [NCT00070174], AAML0531 [NCT00372593], and AAML1031 [NCT01371981]) used a modified version of the CNS disease definitions, in which patients were dichotomously classified for treatment purposes as CNS positive or negative. The CNS-positive group included all patients with blasts on cytospin (regardless of CSF WBC) unless there were more than 100 RBC/μL in the CSF. Patients with 100 RBC/μL in the CSF were CNS positive only if the WBC/RBC ratio in the CSF was greater than or equal to twice the ratio in the peripheral blood. CNS outcomes on COG studies were analyzed using the more traditional CNS1/2/3 definitions.[58]In children with AML, CNS2 disease has been observed in approximately 13% to 16% of cases, and CNS3 disease has been observed in approximately 11% to 17% of cases.[58,59] Studies have variably shown that patients with CNS2/CNS3 disease were younger, more often had hyperleukocytosis, and had higher incidences of t(9;11), t(8;21), or inv(16).[58,59]While CNS involvement (CNS2 or CNS3) at diagnosis has not been shown to be correlated with OS in most studies, a COG analysis of children with AML enrolled from 2003 to 2010 on two consecutive and identical backbone trials found that CNS disease was associated with inferior outcomes, including decreased CR rate, EFS, and disease-free survival (DFS), and an increased risk of relapse involving the CNS.[58] Another trial showed it to be associated with an increased risk of isolated CNS relapse.[60] The COG study did not find traumatic lumbar punctures at diagnosis to have an adverse impact on OS.[58] From an analysis of patients enrolled in the AAML0531 and AAML1031 trials, using the COG definition of CNS involvement, peripheral blood contamination increased the number of patients who were classified as CNS positive and guided to additional intrathecal therapy.[61] In these trials, following past precedence, diagnostic CSF examinations and initial intrathecal administration were done on or before day 1 of induction therapy. Beginning with the COG AAML1831 (NCT04293562) trial, to minimize the contamination risk, the newer guidance is to delay the diagnostic lumbar puncture to day 8, when most patients have cleared their peripheral blood of leukemic blasts. Additionally, a definition of CNS involvement that is more similar to the ALL definition is now in use.

CNS3a: CSF with 5 or more WBC/μL and cytospin positive for blasts in an atraumatic tap (<10 RBC/μL).

CNS disease: CNS involvement at diagnosis is categorized on the basis of the presence or absence of blasts in cerebrospinal fluid (CSF). European cooperative groups have applied ALL definitions of various degrees of CNS involvement to AML, as follows: › CNS3 includes the following three subgroups, which are defined as follows:COG trials (including AAML03P1 [NCT00070174], AAML0531 [NCT00372593], and AAML1031 [NCT01371981]) used a modified version of the CNS disease definitions, in which patients were dichotomously classified for treatment purposes as CNS positive or negative. The CNS-positive group included all patients with blasts on cytospin (regardless of CSF WBC) unless there were more than 100 RBC/μL in the CSF. Patients with 100 RBC/μL in the CSF were CNS positive only if the WBC/RBC ratio in the CSF was greater than or equal to twice the ratio in the peripheral blood. CNS outcomes on COG studies were analyzed using the more traditional CNS1/2/3 definitions.[58]In children with AML, CNS2 disease has been observed in approximately 13% to 16% of cases, and CNS3 disease has been observed in approximately 11% to 17% of cases.[58,59] Studies have variably shown that patients with CNS2/CNS3 disease were younger, more often had hyperleukocytosis, and had higher incidences of t(9;11), t(8;21), or inv(16).[58,59]While CNS involvement (CNS2 or CNS3) at diagnosis has not been shown to be correlated with OS in most studies, a COG analysis of children with AML enrolled from 2003 to 2010 on two consecutive and identical backbone trials found that CNS disease was associated with inferior outcomes, including decreased CR rate, EFS, and disease-free survival (DFS), and an increased risk of relapse involving the CNS.[58] Another trial showed it to be associated with an increased risk of isolated CNS relapse.[60] The COG study did not find traumatic lumbar punctures at diagnosis to have an adverse impact on OS.[58] From an analysis of patients enrolled in the AAML0531 and AAML1031 trials, using the COG definition of CNS involvement, peripheral blood contamination increased the number of patients who were classified as CNS positive and guided to additional intrathecal therapy.[61] In these trials, following past precedence, diagnostic CSF examinations and initial intrathecal administration were done on or before day 1 of induction therapy. Beginning with the COG AAML1831 (NCT04293562) trial, to minimize the contamination risk, the newer guidance is to delay the diagnostic lumbar puncture to day 8, when most patients have cleared their peripheral blood of leukemic blasts. Additionally, a definition of CNS involvement that is more similar to the ALL definition is now in use.

CNS3b: CSF with 5 or more WBC/μL and cytospin positive for blasts in a traumatic tap (≥10 RBC/μL) in which the WBC/RBC ratio in the CSF is more than or equal to twice the ratio in the peripheral blood.

CNS disease: CNS involvement at diagnosis is categorized on the basis of the presence or absence of blasts in cerebrospinal fluid (CSF). European cooperative groups have applied ALL definitions of various degrees of CNS involvement to AML, as follows: › CNS3 includes the following three subgroups, which are defined as follows:COG trials (including AAML03P1 [NCT00070174], AAML0531 [NCT00372593], and AAML1031 [NCT01371981]) used a modified version of the CNS disease definitions, in which patients were dichotomously classified for treatment purposes as CNS positive or negative. The CNS-positive group included all patients with blasts on cytospin (regardless of CSF WBC) unless there were more than 100 RBC/μL in the CSF. Patients with 100 RBC/μL in the CSF were CNS positive only if the WBC/RBC ratio in the CSF was greater than or equal to twice the ratio in the peripheral blood. CNS outcomes on COG studies were analyzed using the more traditional CNS1/2/3 definitions.[58]In children with AML, CNS2 disease has been observed in approximately 13% to 16% of cases, and CNS3 disease has been observed in approximately 11% to 17% of cases.[58,59] Studies have variably shown that patients with CNS2/CNS3 disease were younger, more often had hyperleukocytosis, and had higher incidences of t(9;11), t(8;21), or inv(16).[58,59]While CNS involvement (CNS2 or CNS3) at diagnosis has not been shown to be correlated with OS in most studies, a COG analysis of children with AML enrolled from 2003 to 2010 on two consecutive and identical backbone trials found that CNS disease was associated with inferior outcomes, including decreased CR rate, EFS, and disease-free survival (DFS), and an increased risk of relapse involving the CNS.[58] Another trial showed it to be associated with an increased risk of isolated CNS relapse.[60] The COG study did not find traumatic lumbar punctures at diagnosis to have an adverse impact on OS.[58] From an analysis of patients enrolled in the AAML0531 and AAML1031 trials, using the COG definition of CNS involvement, peripheral blood contamination increased the number of patients who were classified as CNS positive and guided to additional intrathecal therapy.[61] In these trials, following past precedence, diagnostic CSF examinations and initial intrathecal administration were done on or before day 1 of induction therapy. Beginning with the COG AAML1831 (NCT04293562) trial, to minimize the contamination risk, the newer guidance is to delay the diagnostic lumbar puncture to day 8, when most patients have cleared their peripheral blood of leukemic blasts. Additionally, a definition of CNS involvement that is more similar to the ALL definition is now in use.

CNS3c: Clinical signs of CNS leukemia (e.g., cranial nerve palsy, brain/eye involvement, or radiographic evidence of an intracranial, intradural chloroma).

Cytogenetic and molecular characteristics: Cytogenetic and molecular characteristics are also associated with prognosis. For detailed information, see the Genomics of AML section. Cytogenetic and molecular characteristics that are currently used in the COG clinical trials for treatment assignment are shown in Table 5:

Immunophenotype:

Immunophenotype:

A distinctive immunophenotype (initially reported as the RAM phenotype), with high CD56 levels, dim or negative expression of CD45 and CD38, and a lack of HLA-DR expression was associated with a poor prognosis (5-year EFS rate of approximately 20%).[62,63] Most patients with the RAM phenotype have the CBFA2T3::GLIS2 fusion gene.[63,64]

Immunophenotype:

High CD123 expression (quartile 4 vs. quartiles 1–3), in Cox multivariable regression, was shown to be an independent adverse prognostic risk factor for OS, EFS, and relapse risk (RR), although it did not impact remission success. High CD123 expression occurred more frequently in patients with many high-risk cytogenetic and molecular characteristics. High CD123 expression also adversely impacted OS and EFS, but not RR. In patients with low-risk cytogenetic and molecular characteristics, those with high CD123 expression (quartile 4) had significantly worse OS, EFS, and RR.[65]