Journal club

• Acute myeloid leukemia (AML) refers to a group of

hematopoietic neoplasms involving cells committed to
the myeloid line of cellular development

• AML is characterized by clonal proliferation of myeloid

precursors and accumulation of leukemic blasts or
immature forms in the bone marrow, peripheral blood
variety of systemic consequences including anemia,
bleeding, and an increased risk of infection
• AML is the most common acute leukemia in adults

• In adults, the median age at diagnosis is approximately

65 years.

• The incidence increases with age with approximately 1.3

and 12.2 cases per 100,000 population for those under
or over 65 years, respectively.
 INTRODUCTION
• Management of AML involves choosing
between purely palliative care, standard
therapy and investigational therapy (“clinical
trial”)

• Standard therapy:
– CPX 351,
– midostaurin, gemtuzumab ozogamicin, and
venetoclax, when combined with other drugs,
• Knowledge of the likely results with these therapies
is essential in deciding whether to recommend
these or participate in a clinical trial, possibly
including these drugs

• Hence, in the context of established prognostic

algorithms, the results are reviewed with the
recently approved drugs compared with their
predecessors and describe other potential options.
• Some trials have led to changes in what today is
considered “conventional” therapy compared to
even 1-2 years ago

• In older patients decision making has often

included inquiring whether specific anti-AML
therapy should be offered at all, rather than
focusing on a purely palliative approach
• These decisions should be based on the comparative
ratios of benefit to risk with conventional,
investigational, or purely palliative approaches

• Longer survival would qualify as a benefit but also

achievement of a prolonged remission is considered
benefit since it is plausibly associated with longer
survival, reduced frequency of transfusions, and better
“quality of life
• Treatment-related mortality (TRM) resulting in death
from treatment before expected death from disease is
an obvious risk, along with various toxicities of
treatment and a decreased QOL

• A major benefit of many of the recently- FDA

approved therapies for AML is their putative
association with less TRM, fewer toxicities, and better
QOL
 TREATMENT
Purely palliative approach

• Three large US studies involving 4058, 5480 and 8336 patients age
65 or greater (median age 75-80 years), and based on Surveillance,
Epidemiology, and Endpoints Registry (SEER), have reported only
39%-43% of such patients received induction chemotherapy.

• In each study survival was longer in those receiving chemotherapy,

with median survivals of 1-2 months for untreated vs 5-7 months
for treated patients.
• Superior survival following intensive treatment (largely
conventional 7 + 3) in patients aged 70-79 years
regardless of ECOG PS has been reported by the
Swedish AML Registry

• Best supportive care (BSC) only, low-dose cytarabine

(LDAC), or 7 + 3, which could include daunorubicin at
dose of 45 mg/m2 daily × 3; collectively these were
referred to “conventional care regimens”(CCR).
• Dombret et al. randomised 488 patients > or = 65
yrs with newly-diagnosed AML, >30% blasts, and
PS 0-2 in 1:1 ratio between the selected CCR and
azacytidine at the standard dose of 75 mg/m2
daily × 7

• 64% of the CCR patients received LDAC, and 18%

BSC and 18% 7 + 3.
• Thus the evidence suggests little reason to offer
a purely palliative approach to as many patients
age ≥ 65 years with newly-diagnosed AML as has
been the practice in the past

• Improved supportive care, especially better

antifungal therapy have led to declines in TRM
rates following intensive therapy.
• Improvements in survival were observed over
the 1997-2016 period (8 years median follow-
up) in Sweden despite the introduction of no
new therapies, although for unclear reasons
these improvements were limited to men
aged 50-75 years
• Danish population based study (3825 patients)
accounting for the increasing age of AML
patients over the 2000-2015 period found
improved 2-year survival rates in men and
women aged 60-75 years given intensive
induction during this time
New induction therapies that should now be considered
conventional/standard

• Improvements obtained with conventional induction

therapies such as 7 + 3, azacytidine or decitabine,
however been nominal, prompting the introduction of
new induction therapies

• Venetoclax, BCL-2 inhibitor, combined with azacytidine,

should be considered, rather than purely palliative care,
or single-agent azacytidine or decitabine, conventional
management in many newly diagnosed older patient.
• The FDA approval of venetoclax together with
either azacytidine or decitabine or with low-
dose cytarabine (LDAC) was granted for newly-
diagnosed patients age ≥ 75 years or with co-
morbidities “precluding use of intensive
induction therapy”.
• A parallel trial randomized 211 patients (median
age 76 years) considered unfit for intensive
therapy, using similar criteria as in the azacytidine
+/− venetoclax study, in 2:1 double blind fashion
between LDAC + venetoclax or + placebo

• The venetoclax dose was 600 mg daily in 28-day

cycles after a ramp-up period
• The longer survival seen when venetoclax was combined
with azacytidine rather than LDAC might have reflected
azacytidine's superiority to LDAC

• But it also reflected the eligibility of patients for the LDAC +/

− venetoclax trial if they had not responded to azacytidine
(or decitabine) when given for MDS

• Such patients had worse outcomes following venetoclax +

LDAC than those who had never received azacytidine or
decitabine
• Question for the future is whether some
patients benefit more (and some less) from
the combination

• For example patients aged ≥75 seemed to

derive considerably more survival benefit from
the combination than younger patients.
 CPX 351
• In 2017 FDA approved this liposomal formulation of
daunorubicin and cytosine arabinoside for patients
with therapy-related AML (t-AML) or with AML and
“myelodysplasia related changes (AML-MRC)

• Approval followed a trial randomizing (1:1) 309

patients age 60-75 years between CPX and 7 + 3, with
daunorubicin at the now accepted minimally effective
dose of 60 mg/m2 daily × 3.
• Administration of CPX reduced the risk of death
by 30% (HR 0.7, 95% CI 0.6-0.9, and thus P < .05,
medians 9.3 months CPX, 6.0 months 7 + 3)

• CPX appears superior to 7 + 3 in AML-MRC

regardless of whether defined by a history of
MDS, including patients who have and have not
received HMAs, or only by MDS-cytogenetic
changes
• Thus results establish CPX, and not 7 + 3, as the standard
“intensive” therapy for older adults with secondary AML

• The risk of death in patients in whom survival was dated

from allogeneic hematopoietic cell transplant (allo HCT) date
was less in recipients of CPX than of 7+ 3 (HR 0.51)

• This suggests that CPX may be particularly useful in patients

who subsequently receive allo HCT, by being more effective at
reducing MRD than 7 + 3.
 Midostaurin
• The randomized “RATIFY” trial of Stone et al.23
established 7 + 3 + the FLT 3 inhibitor midostaurin as
conventional therapy for adults age < 60 years with
either a FLT3 (TKD) mutation or a FLT3 (ITD) regardless
of the ratio of affected to unaffected alleles

• The superiority of midostaurin was independent of allo

HCT with best results seen in patients receiving allo
HCT in CR1 after receiving midostaurin
• Questions remaining in the 2019 update25 were the
need for midostaurin maintenance26 and whether the
benefit of midostaurin would also be seen in adults
age > 60 years.

• To address these questions The German AMLSG

administered 7 + 3 + midostaurin to 86 patients aged
61-70 years and 198 patients aged 18-60 years with a
FLT3 ITD.
• All patients entering CR or CRi to receive allo HCT
followed by 12 months of midostaurin maintenance

• The CR/CRi rate was 76% and was similar in older and
younger patients and unaffected by FLT3 AR < vs > 0.5.

• Allo HCT was performed in 58% of those entering CR

with the remaining patients receiving “high-dose”
cytarabine(HDAC) post-remission therapy followed by
midostaurin maintenance
• Best results were seen in patients, including
those age 61-70 years, who received HCT in CR1,
particularly if they received midostaurin
maintenance.

• Thus the best therapy for all patients age < 70

years includes allo HCT and midostaurin
maintenance.
 Gemtuzumab ozogamicin (GO)
• An individual-patient meta-analysis of five randomized
trials including 3325 adults median age 58 comparing 7 + 3
or FLAG-ida +/− GO, found, that although CR rates were
similar ±GO, significant reductions in risk of relapse are
seen with GO  to longer survival

• Benefits were confined to those with UK Medical Research

Council-defined “favorable” cytogenetics in whom survival
probability at 6 years was 55% without, vs 76% with GO
and with intermediate cytogenetics.
• Administration of 3 mg/m2 GO on days 1, 4,
and 7 of chemotherapy was associated with
the least toxicity and equal benefit.

• Resulted in FDA approval of GO for adults with

CD33 positive AML ->consists of an anti CD33
antibody attached to a toxin (calicheamicin)
• Addition of GO was beneficial in the ELN2017
“favorable” group and the ELN 2017
intermediate group, but not in the ELN2017
adverse group

• Benefit seen on addition of GO in patients

with mutations in NPM1, CEBPA, FLT3 ITD or
TKD, NRAS, KRAS, and SRSF2.
 Ivosidenib
• The FDA approved this IDH1 inhibitor as a single agent
for IDH1 mutated AML occurring in a very similar
population for which it granted approval for venetoclax
+ HMA or LDAC

• At a dose of 500 mg daily given to 34 patients, median

age 77 years, who remained on study for a median of
4.5 months (up to 40 months), the CR rate was 30%
and CR + CRh rate was 42%
• IDH1 mutations disappeared in 5/10 patients entering
CR, 4/4 entering CRi, and 0/16 achieving neither

• Nine of 21 patients who were transfusion dependent

pre-treatment became transfusion independent for at
least 56 days

• Seven of 12 who were transfusion independent at

study entry remains so for at least 56 days
• ‘’Differentiation syndrome”(DS) analogous to
that which occurs following treatment of acute
promyelocytic leukemia with all-trans retinoic
acid or arsenic trioxide was the major unique
toxicity (occurring in 18%, severe in 9%)

• Readily responsive to steroids and required

temporary discontinuation of only in the three
with severe DS.
 Glasdegib
• A randomized trial in “unfit” patients similar to
those in the venetoclax and ivosidenib studies
showed longer survival patients randomized to
the hedgehog pathway inhibitor glasdegib + LDAC
vs LDAC alone, leading to FDA approval of
glasdegib
A good/intermediate cytogenetic risk and B poor cytogenetic
risk. 
• Some remaining issues are still present

• Primary among these is the definition of

“unfitness” for intensive chemotherapy
 The issue of “fitness”
• Criteria for unfitness in the venetoclax trials were
either age ≥ 75 years or co-morbidities, both
presumably precluding use of intensive induction

• Ivosidenib and glasdegib are approved for the

same population

• Principal consequence of unfitness would be TRM

• The effect of age alone on TRM by day 28 has been shown
to be less than the effect of performance status (PS)

• Trial leading to FDA approval of venetoclax + either

azacytidine or decitabine noted only 16% of patients had
PS 2 and none had PS 3-4.

• Four percent of patients in the LDAC +/− venetoclax trial

had PS 3, although 44% had PS 2, with patients with PS 2-3
having shorter survival than those with PS <2
• Because the effect of age can be confounded
with the effect of other covariates the 2017
European LeukemiaNet AML guidelines say
that “age alone should not be the only
determinant of fitness for intensive induction”.

• Fitness must be judged in the context of efficacy

• “Favorable” cytogenetics are extraordinarily rare in IDH-
mutated AML

• But some patients otherwise meeting eligibility criteria but

with “favorable” risk cytogenetics were likely excluded from
the venetoclax and ivosidenib trials, in favor of intensive
induction

• This implies patient considered “unfit” for such therapy, can

be considered “fit” if the benefit/risk ratio is sufficiently high,
as with favorable cytogenetics
• Observational data suggest some older patients
with relatively poor AML Comorbidity Indices
(AMLCI) live longer when given more intense
therapy than when given venetoclax

• Multivariate models provided criteria for

determining those who are fit for intense
induction
• It is often assumed patients given less intense induction
would have superior QOL

• El-Jawhari et al. analyzed QOL, anxiety, and depression in

patients ≥60 during the first 24 weeks following initiation of
remission induction therapy

• Found that QOL and anxiety generally improved (depression

stayed the same) regardless of whether intensive
(anthracycline+ cytarabine) or less intense (HMA) induction
was given.
 THERAPY ISSUES
Conventional therapy vs investigational therapies
• Advent of therapies such as venetoclax + azacytidine or
ivosidenib implies fewer patients should be offered
purely palliative care

• The question remains whether a given patient should

be offered conventional therapy, including those newly
identified as such, or investigational therapy on a
clinical trial.
• The main reason to refer a patient for a trial is
dissatisfaction with the results of conventional
therapy

• For example, median survival in patients given

azacytidine + venetoclax arm in the recently
reported randomized trial was 14.7 months vs
9.6 months for azacytidine + placebo;
– at 2 years probability of survival was 40% vs 30%.
• The median does not give a complete account,
but represents a convenient picture of
probable outcome

• There is limited ability to know who will do

much better or much worse than the median
• Conventional prognostic factors, such as
cytogenetics (“intermediate” vs “adverse”)
remain prognostic when patients receive CPX,
venetoclax + HMA, or + LDAC

• Failure to respond to HMA for prior MDS is

prognostic in the case of venetoclax + LDAC and
possibly ivosidenib.
• Patients with the prognostically unfavorable TP53 or ASXL1
mutations appear more likely than others to be resistant to
or have only short remissions following venetoclax + HMA

• The choice between conventional and investigational

therapy is largely subjective, particularly because patients
may vary in what they value as benefit (eg, survival vs QOL)
and the amount of risk they are willing to accept to achieve
a benefit
 ELN 2017 prognostic system to assess
expected prognosis with conventional
therapy
• ELN 2017 provides a useful guide to aid in the choice
between conventional and investigational therapy

• Patients are divided into “favorable”, “intermediate”

and “adverse” groups.

• The German AMLSG recently validated the prognostic

significance of ELN2017 for remission, survival, and
relapse-free survival
• Poor prognosis of patients with TP53 mutations
(TP53 is located on the short [p] arm of
chromosome 17) or complex cytogenetics, are
highly associated with each other,

• So these should be considered a “very adverse”

group, as distinct from the “adverse” group.
• Those patients in the ELN favorable group based
on presence of an NPM1 mutation and a FLT3 ITD
AR < 0.5 have a favorable prognosis only in the
presence of a normal karyotype;

• Adverse cytogenetics is associated with the

same prognosis regardless of whether an NPM1
mutation is found
• Multivariate analyses indicate that older age is itself
associated with poorer relapse-free, and overall, survival

• The SWOG and UK MRC/NCRI data indicate patients age

> 65 years with the presumed “favorable” constellation
of an NPM1 mutation, no FLT3 ITD, and normal
cytogenetics have inferior survival and RFS survival than
patients age 55-65 years and < 55 years with the same
findings
• Where patients expected to do relatively poorly with
previous conventional therapies (eg, 7 + 3) also did
relatively poorly with newer conventional therapies
(eg, venetoclax + azacytidine, CPX351, ivosidenib).

• This suggests ELN2017 is likely to be useful in

predicting outcome even in patients given these
newer therapies
• Efforts to quantify the roles of epigenetic (eg,
methylation), gene expression, or proteomic
profiling in informing prognosis have been
ongoing

• Study of single cells, for example AML “stem

cells”, rather than bulk populations, is more
complex but will be particularly informative
 Recommendations for initial induction
therapy
• A clinical trial is not necessarily inappropriate in any
ELN2017 prognostic group since results are suboptimal
even in the ELN favorable group for patients age > 65 years

• A trial becomes crucial in the ELN intermediate and,

particularly, the ELN adverse group.

• The decision whether a patient should receive more vs less

intense induction depends on several factors, probably
most importantly the risk of TRM.
• A still unsettled question is whether 7 + 3 or a regimen
including higher doses of cytarabine, such as FLAG-IDA,
is the preferable intense induction regimen.

• The SWOG trial 1203 randomized 754 adults age < 60

years among 7 + 3 (with a daunorubicin dose of 90
mg/m2), idarubicin (12 mg/m2 daily × 3) + cytarabine
1.5 g/m2 daily by continuous infusion × 4 days (IA) and
IA + vorinostat.
• Allogeneic hematopoietic cell transplant rates in CR
were similar in each arm (about 48%) and there were
no differences in EFS, RFS, or survival among the three
arms, including in patients with NPM1, FLT3, or CEBPA
mutations or intermediate or adverse cytogenetics

• Patients with “favorable” cytogenetics having inferior

EFS,RFS, or survival if in the IA arms
• The NCRI/MRC group in the UK found reduced
relapse rates with FLAG-IDA than with 10 days
of standard cytarabine + daunorubicin.

• However, there were no differences in survival

possibly because of higher treatment-related
mortality rate in CR in the FLAG-IDA arm.
• A 1205 patient randomized NCRI trial found no
difference, other than more TRM in the higher
dose arm, between 7 + 3 using daunorubicin doses
of 90 mg/m2 vs the usual 60 mg/m2 each daily × 3

• But patients with FLT3 ITD had less relapse leading

to longer survival if given the 90 mg/m2 dose.
• Montalban-Bravo et al have reported that in
patients with MDS and NPM1 mutations
induction with higher doses of cytarabine,
rather than HMA, was associated with longer
survival and EFS
Ongoing clinical trials in newly-diagnosed
AML
 Goal of induction therapy
• For many years CR was considered the goal of induction
therapy.

• Recent years have seen the adoption of responses less than CR,
for example CRp or CRi

• The category CRh in which platelet count is >50 000 and ANC >
500 per μL but not meeting requirements for CR (ANC > 1000,
platelet count >100 000 per μL) has appeared most recently.
• The FDA approved ivosidenib and enasidenib based on rates
of CR + CRh.

• Walter et al. reported CR was associated with longer

relapse-free survival, and to a less extent survival, than CRp

• However, CRp was associated with longer survival than

resistance, thus validating CRp as a clinically relevant
response.
• In general, CR without MRD is associatedwith longer
remissions, RFS, and survival than is CR with MRD

• The prognosis of patients who receive allo HCT with

MRD, although in CR by conventional morphologic
criteria (<5% blasts), appears approximately the same
as those with morphologic relapse and much worse
than patients who are transplanted in morphologic CR
but without MRD
• ELN2017 thus recognizes CR without MRD as
a distinct response category.

• This response should be the goal of initial

induction therapy
 Quantifying risks of relapse and
NRM to inform the allo HCT decision

• Allo HCT is recommended based on the presumption

the reduced risk of relapse will be greater than the
increased risk of NRM and morbidities such as GVHD.

• The potential morbidity from GVHD has been

recognized by the introduction of a new endpoint
(GVHD-free, relapsefree survival [GRFS]
• The most sensitive means for MRD detection
rely on qPCR technology

• Data suggest MFC and NGS are

complementary at least in adults age < 65
years
• General recommendation is to offer allo HCT to all
ELN2017 intermediate and adverse risk patients.

• In contrast, the risk of relapse without allo HCT in

the ELN 2017 favorable subgroup is generally
considered too low to justify the risk of allo HCT.

• MRD assessments can refine these

recommendations
 Preventing post allo HCT relapse
• Relapse remains the principal cause of failure
after allo HCT

• For years there has been debate whether the

reduction in NRM afforded by reduced intensity
conditioning (RIC) regimens is outweighed by their
potential to increase relapse.
• Comparing myeloablative (MA) and RIC in patients according to
their pre-HCT MRD status as assessed by NGS Hourigan et al.
found MA decreased relapse risk and improved survival and RFS
only in patients who were NGS positive.

• Comparing seven nontotal body irradiation containing regimens

they concluded patients with “acceptable” HCT-CI scores should
be conditioned with “Bu4/ Cy”, “Flu/Bu4”, or Flu/Mel, with
younger patients possibly also benefitting from Flu/Mel.
• Treosulfan in combination with fludarabine and
relatively low dose TBI is another conditioning
regimen

• Several studies are targeting the myeloid

surface antigens CD33 and CD45 with alpha
particles such as actinium-225 and astatine-211
• Madiarz et al. randomized 60 adults age < 70 years with
FLT ITDs in remission 1-2 months after allo HCT to receive
usual care +/− midostaurin 50 mg twice daily;

• Median exposure was 10 months.

• Relapse rates were 24% in the control and 11% in the

midostaurin arm,
• Craddock administered azacytidine to 51 patients
undergoing allo HCT, finding a decreased relapse risk
(HR 0.30, 95% CI 0.10-0.85) with similar improvement
in RFS in patients demonstrating a CD8+ T-cell response
to tumor antigens.

• This is because of azacitidine's ability to upregulate

potential AML-associated antigens thus inducing a
CD8+ T cell response augmenting the GVL effect,
 Autologous (auto) HCT
• Despite lack of an obvious GVL effect, auto HCT
provides more anti AML effect than chemotherapy,
at least in “favorable” and intermediate risk patients

• Survival after auto HCT can be comparable to that

seen after allo HCT

• Allo HCT done in second CR(CR2) in up to 30% of

patients whose disease has recurred after auto HCT
• Patients in the ELN2017 intermediate (and
possibly some in the ELN favorable group)
who are MRD negative after initial therapy
might be considered for auto HCT rather than
allo HCT.
Management of relapsed/refractory AML
THANK YOU