Aml and bone marrow transplant

AML and Bone Marrow
Transplant
Joydeep Ghosh
Registrar
Hemato-oncology and BMT unit
Apollo Gleneagles Cancer Hospital

When do we call it AML?
 Clinical features of weakness ,
fatigability, wt. loss, easy bruisability,
fever, bone pain , hepato-
splenomegaly, lymphadenopathy etc
 Lab features :
◦ Blood/BM: more than 20% myeloblasts
◦ Less than 20% blast but with recurrent
cytogenetic abnormalities like t(8;21),
t(15;17), t(16;16), inv 16

Optimal induction & post-
remission therapy for AML in first
remission
 The therapy of AML is based on
maximally tolerated induction and post-
remission therapy, all given within a few
months from diagnosis.
 Ultimate cure of the disease depends on
disease eradication through the
administration of post-remission therapy
 The greatest challenge: maintain the
remission

Induction Therapy
 Began in late 1960s with anthracycline
and cytarabine
 CALGB trials have established that
continuous infusion cytarabine was
most effective; 3 + 7 was more
effective than 2 + 5 regimen
 Standard of care: DNR 45 mg/m2
intravenously for 3 days and cytarabine 100mg/m2
by continuous infusion for 7 days.
◦ With this regimen 60% to 80% of young adults and 40% to
60% of older adults can achieve a CR

Which anthracycline?
 In the early 1990s, a series of
randomized studies compared 45 or 50
mg/m2 of DNR with a variety of newer
agents, including idarubicin,
mitoxantrone, aclarubicin or amsacrine.
 Every one of these was superior in CR
rate, DFS, OS or in the number of
courses needed to get into CR.
 Even after all these trials, it is surprising
that DNR at 45 g/m2 remained as the
standard of care for so many years

Addition of gemtuzumab?
 In the MRC AML-15 study of younger
adults, 1115 patients were randomized in
induction to receive, or not, gemtuzumab
ozogamicin (GO) in addition to the
induction regimen.
 Results: similar CR in both arms, but a
significantly improved DFS among
patients receiving GO—51% versus 40%
at 3 years (P = .008)
 Do not seem to benefit patients with
unfavourable cytogenetics.

Alternative regimens??
 First, there is no evidence that any form
of induction therapy is better than the
standard combination of anthracyclines
and cytarabine
 Secondly, for fit older patients
attenuation of induction therapy is
definitely not recommended.
◦ A recent comprehensive population-based study from the
Swedish Acute Leukemia Registry 5 reported the outcome for
older patients with AML. The survival was improved for patients
up to 80 years of age in the geographical regions where most
were given standard induction therapy, and the early death rate
was also lower with intensive therapy than with palliative therapy

Newer agents?
 Clofarabine, laromustine and
rapamycin have demonstrated activity
in patients with more advanced AML
and are currently being investigated
as agents in induction in an attempt to
further improve the overall results and,
especially, ameliorate the toxicity.

Post remission therapy:
 The need for any post-remission
therapy was established in the
landmark study conducted by the
ECOG in 1983 .
 Options:
◦ Maintenance chemotherapy
◦ HSCT

Chemotherapy
 A variety of studies have suggested
that increasing the intensity of post-
remission therapy prolongs remission
duration and increases the likelihood
of cure in adults up to age 55 or 60
 Choice of drugs and mode of
administration are, as a rule, not
dependent on the prognostic factors

Dose/drug
 CALGB has shown that 3-4 cycles of
HiDAC(3gm/m2) is better than
intemediate or low dose cytarabine in
terms of OS
 However,
◦ Non-cytarabine regimens &
◦ Single cycle HiDAC have shown equal
efficalcy in some RCTs.

How much consolidation?
 Finnish Leukaemia Group
 Patients were given 2 courses of
consolidation and were then
randomized between receiving
additional 4 cycles of consolidation vs
observation
 No difference was seen in survival
from randomization

Dose attenuation?
 The problem of
treating older adults
relates most
importantly to the
inability to maintain
a remission. While
CR can be
achieved in 40% to
60% of patients on
clinical trials,
depending on age
and prognostic
factors, the DFS is
only 6to 9 months
and with an OS of 7
to 10 months

Maintenance therapy:
 AML is clearly curable without maintenance
therapy and such an intervention is, in most
centres, not used routinely, especially in
younger adults.
 The issue of maintenance therapy is
particularly pertinent for older patients.
 An important study by the European
Organization for Research and Treatment of
Cancer(EORTC) and the HOVON group
demonstrated an improved DFS after
maintenance with low-dose cytarabine,
although the OS was not significantly
improved.

Role of Allo HSCT
 Allogeneic hematopoietic stem cell
transplantation (allo HSCT) from an
HLA-matched related donor provides the
most potent anti-leukemic effect of any
post-remission therapy in AML, as
demonstrated by the lowest rates of
relapse.
 Graft vs leukemia plays and important
role here.
 Provides the best chance of long-term
survival

Pros and cons:
 Disadvantages :
◦ Graft failure
◦ GVHD
◦ Peri-transplant mortality rate
 The current recommendations for
the performance of allo HSCT for
patients in CR1 are limited to those
whose risk of relapse significantly
exceeds the incremental mortality
from allo HSCT over standard
chemotherapy

FAQs
 Which patients should be offered this
in CR1?
 How much, if any, additional post-
remission therapy should be
administered prior to allo HSCT?

Indications
 The decision to undergo an allo HSCT
will depend on the prognostic factors
at diagnosis and, no less importantly,
at the point of achieving CR1
 Thus, allo HSCT in CR1should be
considered in patients with
unfavorable cytogenetics and those
with intermediate-risk cytogenetics,
except possibly those with the
NPM1+/Flt3-ITD– subgroup

Place of unrelated transplants
 The German AML01/99 study : addressed the
value of unrelated HSCT for AML in CR1.
 In this study patients with unfavorable
cytogenetics, or those with residual leukemia on
the day 15 post-induction marrow, were assigned
to receive an allo HSCT from a matched sibling,
if such a donor were available. Otherwise,
patients were to receive a matched unrelated
donor transplant, if a suitable donor could be
found, or an auto HSCT.
 The 4-year OS was 68% with sibling allo HSCT
and 56% with an unrelated allo HSCT; both
significantly better than an auto HSCT or
chemotherapy

Sibling un-available situation
 Genetically haploidentical transplants
present another alternative for patients
with a poor prognosis for whom no si
 Another evolving option for patients
who do not have a sibling donor is the
use of unrelated umbilical cord blood
transplantation.

 The decision to undergo an allo HSCT
for AML in CR1must be based on a
careful consideration of the evidence.
If the evidence suggests a clear
benefit for this in CR1 , such
transplants should preferably be
performed at that time and not
“reserved” for CR2.

Place of Auto HSCT
 Most of the major prospective studies
published over the past decade have
described a lower relapse rate for
patients undergoing an auto HSCT in
comparison with chemotherapy and a
meta-analysis of six trials, including 4410
patients, also indicated that auto HSCT
is associated with a modest
improvement in DFS.
 In most prospective studies of auto
HSCT the OS was not significantly

To conclude…
 The major curative potential is while
patients are in CR1; once in relapse,
the options are very limited
 Cytogenetics is cornerstone of the line
of management
 Role of HSCT to be judged as per the
clinical scenario

Aml and bone marrow transplant

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