Adult all and phildelphia +ve all modified latest

Introduction
 The proportion of ALL among adult patients
diagnosed with acute leukemia at reporting
institutions from 16 Indian studies ranged from
7.3% to 57.8%.
 Most studies were performed in Northern India
 Male preponderance (range, 57%-80%),
 Predominance of B-ALL (range, 65.2%-75.9%).

 The complete remission rates ranged from 46.7%
to 91.4%
 median overall survival ranged from 7 to 46
months.
 The overall relapse rates were 24.3% to 57.1%
within median time of 9 to 24 months
 Bone marrow --> the most frequent relapse site

PRETREATMENT EVALUATION
 In addition to a history and physical examination, one should perform
the following pretreatment studies in patients with ALL:
 Laboratory studies include a
 complete blood count with differential,
 liver and renal function and electrolytes,
 glucose,
 lactate dehydrogenase (LDH),
 calcium, phosphorus, uric acid, albumin and total protein, and
 serology for hepatitis B, herpes simplex virus (HSV) and
cytomegalovirus (CMV) infection.
 Human leukocyte antigen (HLA) typing should be performed for
patients who are candidates for future hematopoietic cell
transplantation (HCT).

 Routinely test thiopurine methyltransferase (TPMT)
enzyme activity (phenotype) before starting 6-
mercaptopurine (6-MP), and one should use reduced
doses for patients with low or absent activity.
 An acceptable alternative is to reserve testing for patients
with unexpectedly severe or prolonged myelosuppression
following 6-MP.
.

 A chest radiograph, an electrocardiogram (EKG),
and a study of cardiac function (EF measured by
echocardiogram or radionuclide ventriculography)
should be performed at baseline, especially for
patients with a
 cardiac history,
 prior anthracycline exposure, or
 cardiovascular symptoms

 Patients with neurologic signs or symptoms should
undergo imaging studies to evaluate for meningeal
disease, or central nervous system bleeding.
 Lumbar puncture is indicated in all patients to
examine the cerebrospinal fluid (CSF) for leukemic
involvement.
 Care must be taken to avoid contaminating the CSF
specimen with peripheral blood if blasts are present.
 CSF should be sent for both cytology (examination of
stained cytospin slides) and flow cytometry.

RISK STRATIFICATION
 ALL is a heterogeneous disease and outcomes
vary by clinical, cytogenetic, and molecular
features.
 Patients should be evaluated at the time of first
complete remission (CR1) to determine their
expected risk of relapse

 Patients with any of the following characteristics
are considered to have high-risk disease:
 High white blood cell count at diagnosis (ie,
>30,000/microL in B-ALL or >100,000/microL in T-
ALL).
 Clonal cytogenetic abnormalities – t(4;11), t(1;19),
t(9;22), or BCR-ABL gene positivity. The prognostic
value of t(1;19) in adult ALL is less clear than in
pediatric ALL [3].
 BCR-ABL1-like (Ph-like) gene signature.

 Progenitor-B cell immunophenotype (eg, blasts
expressing membrane CD19, CD79a, and
cytoplasmic CD22, but not CD10).
 Length of time from start of induction therapy to
attainment of CR greater than four weeks
 Older age – >60 years old is high risk, 30 to 59
years old is intermediate risk.
 MRD – A post-remission bone marrow MRD level
≥10-4

INDUCTION CHEMOTHERAPY
 Once the diagnosis of acute lymphoblastic leukemia
(ALL) is established, induction chemotherapy is
given with the following primary goals:
 Rapid restoration of bone marrow function, using
multiple chemotherapy drugs at acceptable toxicities, in
order to prevent the emergence of resistant subclones.
 Use of adequate initial and prophylactic treatment of
sanctuary sites, such as the central nervous system
(CNS), since CNS relapse is associated with a poor
prognosis

 Induction therapy aims to reduce the total body leukemia
cell population from approximately 1012 to below the level
of 5 percent blasts, which corresponds with a total load of
about 109 cells.
 The remaining burden of leukemia cells (ie, measurable
residual disease, MRD; also referred to as minimal
residual disease) will lead to relapse if no further therapy is
administered.
 Reducing the level of residual ALL in the bone marrow at
the end of induction to <0.01 percent as measured by flow
cytometry, has been shown to predict for better long-term
outcomes.

 Combination chemotherapy is the primary
treatment modality for patients with ALL.
 Multiple induction regimens have been
developed, most often based on pediatric
regimens, but they have not been directly
compared in a prospective randomized trial.
 As such, there is no single best regimen for
induction therapy in ALL and patients should be
encouraged to participate in clinical trials
whenever possible.

 Most chemotherapy regimens for ALL contain vincristine, a
glucocorticoid (ie, prednisone or dexamethasone ), asparaginase
and an anthracycline
 In addition, some form of central nervous system (CNS)
prophylaxis is incorporated.
 With these regimens, more than 80 percent of newly diagnosed
adults with ALL enter complete remission (CR).
 Protocols that have added other agents
(eg, cyclophosphamide, cytarabine, methotrexate, 6-
mercaptopurine, etoposide and teniposide) have not improved the
CR rate; however, some have demonstrated a faster time to
achievement of CR, which may be associated with prolonged
remissions

The following are examples of the most commonly used
regimens:
●Cancer and Leukemia Group B (CALGB) study 8811
or 9111 ALL regimen
●CALGB study 10403 ALL regimen for adolescents and
young adults (AYA)
●Dana Farber Cancer Institute (DFCI) ALL Consortium
study for patients 18 to 50 years old
●Standard or augmented Berlin-Frankfurt-Munster
(BFM), which has been used by the Children's Cancer
Group for children and adolescents

●Hyperfractionated cyclophosphamide, vincristine, doxorub
icin and dexamethasone (Hyper-CVAD) alternating with
high-dose methotrexate and cytarabine
●French GRAALL 2003 regimen for younger adults
●French GRAALL 2005 regimen for adults up to 55 years
old
● Linker 4 drug regimen

General considerations
Anthracyclines
 Inclusion of an anthracycline in induction therapy
achieves superior outcomes compared to the same
regimen without an anthracycline
 In CALGB 7612, addition of daunorubicin to a
regimen that included vincristine, prednisone, and L-
asparaginase for adults with ALL achieved
 superior rates of CR (83 versus 47 percent) and
 Superior median remission duration (18 versus 5
months), when compared with those who did not
receive daunorubicin

 Attempts have been made to escalate the dose of
daunorubicin but any benefit has been balanced
by greater toxicity [12].
 Doxorubicin, daunorubicin, rubidazone,
and mitoxantrone appear to produce comparable
results

Cyclophosphamide
 A prospective trial randomly assigned treatment
of
 778 adults with newly diagnosed ALL
 to receive induction therapy
(vincristine. prednisone, daunorubicin,
asparaginase) with or without a single dose
of cyclophosphamide
 similar rates of CR (81 and 83 percent) and eight-
year disease-free survival (DFS; 34 and 31 percent)

 Other trials that have investigated the addition of
cyclophosphamide into the treatment regimen of ALL have
suggested that cyclophosphamide may increase the rapidity
with which CR is achieved and may increase remission
duration.
 Two sequential cooperative group trials involving 379 adults
reported a
- -> similar CR rate (85 percent) and a median remission duration of
28 months .
 However, the median remission duration varied according to
the rapidity of CR attainment, being
 34 months for the 237 patients who achieved CR within 30 days,

Asparaginase
 For adults, asparaginase is a component of CALGB,
DFCI, BFM, GRAALL 2003 and 2005, and modified
Hyper-CVAD regimens; it is not included in the
standard Hyper-CVAD regimen.
 Asparaginase is a key component of the ALL
regimens for children leading to superior CR and DFS
rates
 The importance of asparagine depletion in adults was
illustrated in a prospective study of pegylated
asparaginase that demonstrated
 a significant improvement in median OS ( 31 versus 13
months) in those patients who achieved plasma

 Asparaginase can be associated with
 allergic reactions,
 coagulopathies,
 acute pancreatitis, and
 increased liver transaminases
 induces a hypercoagulable state --> catastrophic
thrombosis of the inferior vena cava or the superior
sagittal sinus
 In addition, adults receiving asparaginase
commonly develop fatigue, anorexia, confusion,
and listlessness.

 There are three formulations of asparaginase
available, each with different half-lives:
 Native Escherichia coli asparaginase – Half-life
approximately one day
 Erwinia asparaginase – Half-life approximately 14 hours
 Pegylated Escherichia coli asparaginase
(pegaspargase) – Half-life approximately six days

 Calaspargase pegol is an asparagine-specific enzyme
that enables a longer interval between doses
compared to other available pegaspargase products.
 Calaspargase pegol was approved by the US Food
and Drug Administration for treatment of ALL in
 pediatric and young adult patients
 age 1 month to 21 years
 based on achievement and maintenance of nadir serum
asparaginase activity >0.1 units/mL
 Dose : 2500 units/m2 intravenously every three
weeks

 Pegylated asparaginase has become the preferred
preparation for most circumstances, because
 it is less immunogenic
 equal or greater efficacy when compared with the other
formulations
 In addition, patients who receive pegylated
asparaginase appear to be less likely to develop
antibodies that result in increased clearance of
asparaginase from the circulation and possibly to
reduced efficacy

 Pegylated asparaginase – A reasonable schedule for
pegylated asparaginase would be either 2000
units/m2 given every two weeks or 1000 units/m2 given
weekly.
 These doses would result in asparagine depletion in the
vast majority of adults for a two-week period.
 Generally, this is intercalated between courses of more
cytotoxic therapy or the combination of vincristine plus
glucocorticoids.
 The dose is capped in larger adults at 3750 units total (one
vial).
 Older patients have had fewer adverse events when lower
doses were used.

 Nonpegylated preparations – Nonpegylated
asparaginase preparations have a shorter half-life and
require daily or every other day administration.
 They are also more immunogenic.
 The dose of L-asparaginase used varies from 6000
units/m2 (in the CALGB regimen) to a fixed dose of
20,000 units (in the modified Hyper-CVAD regimen

 In patients who develop antibodies to
asparaginase, serum drug levels are
nondetectable or minimal, which suggests that
there is no active drug available
 If asparaginase levels are nondetectable with
one preparation, an alternative preparation may
be more effective.

 The best time to measure asparaginase activity depends
on the formulation, dosing, and schedule of asparaginase
used.
 When using pegylated asparaginase, asparaginase
activity is measured 7 and 14 days after the first dose
during induction and seven days following every
reintroduction after a break in asparaginase treatment
 A level below 0.1 international units (IU)/mL on day 7
and/or undetectable levels on day 14 are consistent with
silent inactivation

 Because of the relatively high incidence of infusion
reactions, asparaginase should only be administered in
a setting where anaphylaxis can be appropriately
managed
 Subcutaneous or intramuscular administration appears
less likely to cause anaphylactic reactions than
intravenous dosing. Premedication with glucocorticoids
is helpful.
 Patients who develop an anaphylactic reaction to one
preparation may be considered for treatment with
another preparation.

Choice of glucocorticoid
 Dexamethasone and prednisolone are the glucocorticoids
most often used, but the optimal glucocorticoid, dose, and
schedule for adults is not well defined.
 Prednisone was incorporated most ALL induction
regimens, but dexamethasone penetrates the blood-brain
barrier more effectively.
 In children, patients treated with dexamethasone have
lower rates of relapse and fewer thrombotic complications
than those treated with prednisone [49-54]

 On the other hand, dexamethasone has not
demonstrated a survival benefit and is associated
with a higher rate of avascular necrosis of hips and
shoulders, which is seen commonly in adolescents
and young adults than in younger children.

Addition of rituximab for CD20+ ALL
 For younger adults (<60 years of age) with CD20-
positive ALL, we suggest the addition of rituximab to
standard induction regimens.
 Rituximab appears to improve outcomes for younger
adults with CD20-positive ALL, based on
nonrandomized and randomized studies in which
rituximab was added to hyper-CVAD, BFM, and
GRAALL regimens.
 The benefit of rituximab in older patients with ALL is
not proven

 A single center study:
 Adults <60 years with de novo Philadelphia
chromosome negative precursor B cell ALL
 a modified hyper-CVAD regimen plus rituximab Vs
standard hyper-CVAD without rituximab
 superior survival rates for modified hyper-CVAD
+rituximab

 In contrast, older adults (≥60 years) did not
appear to benefit from the addition of rituximab.
 The GMALL study group subsequently evaluated
 196 standard-risk patients and 67 high-risk patients
 cohorts that had received rituximab with
chemotherapy had significantly higher molecular
remission rates and longer OS [55,56].

 In a multicenter randomized trial,
 209 adults with previously untreated CD20-positive,
Philadelphia chromosome negative, precursor B cell ALL
 randomly assigned to the pediatric inspired GRAALL regimen
with or without the addition of 16 to 18 infusions
of rituximab spanning induction through maintenance [57]

 A higher percentage of patients treated with rituximab
received an allogeneic hematopoietic cell
transplantation (HCT) in first CR (34 versus 20
percent).
 At a median follow-up of 30 months, the addition of
rituximab resulted in:
 Similar complete response rates (92 versus 90 percent).
 No difference in non-relapse mortality at two years (12
versus 12 percent).

 Lower cumulative incidence of relapse at four years (25
versus 41 percent).
 Longer event-free survival (EFS; 55 versus 43 percent at
four years; HR 0.52).
 No statistically significant difference in OS (61 versus 50
percent at four years; HR 0.70) among the group overall.
 When patients who received allogeneic transplant in
first CR were censored at the time of transplant, OS
was improved in the rituximab arm (HR 0.55).

CALGB 8811/9111 ALL regimen
 The Cancer and Leukemia Group B (CALGB)
8811/9111 ALL regimen uses a five-drug
combination modified from regimens used for
high-risk pediatric ALL
 Treatment is given in five courses that span 24
months.

 A phase II multicenter prospective clinical trial was
performed in
 197 patients with newly diagnosed ALL
 age 16 to 80; median age 32 [13].
 CR was obtained in 85 percent,
 7 percent were refractory and 9 percent died during
induction.
 After a median follow-up of 43 months,
 the median survival was 36 months and the median
remission duration was 29 months..

 Severe (grade 3/4) toxicities included
 leukopenia (98 percent),
 thrombocytopenia (94 percent),
 anemia (65 percent), infection (54 percent), and
 increased transaminases (25 percent).
 There were eight episodes of clinically significant
pancreatitis.
 Most deaths were related to gram-negative bacteremia or
fungemia in older patients.

 In CALGB 9111,
 198 adults with untreated ALL
 median age, 35 years;
 randomly assigned to receive either placebo or G-CSF (5
mg/kg/d) subcutaneously, beginning four days after
starting intensive remission induction chemotherapy and
continuing until the neutrophil count was >1000/microL for
two days .

 Patients initially assigned to G-CSF then continued to
receive G-CSF through two monthly courses of
consolidation therapy.
 Compared to the patients assigned to placebo, patients
who received G-CSF had a
 higher rate of CR and fewer deaths during remission
induction,
 shorter median time to recover neutrophils >1,000/microL
(16 versus 22 days),
 shorter durations of neutropenia and thrombocytopenia, and
 fewer days in the hospital (median, 22 versus 28 days).
 However, after a median follow-up of 4.7 years, there
were no significant differences in either the DFS or

CALGB 10403 regimen
 To address the feasibility and efficacy of using a
pediatric treatment regimen for AYA patients with
newly diagnosed B cell and T cell ALL administered
by adult treatment teams
 CALGB 10403, used the identical doses and schedule
in the Children's Oncology Group study AALL0232

BFM regimen
 The Berlin-Frankfurt-Munster (BFM) regimen is
frequently used for the treatment of pediatric ALL and
can be considered for young adults with a good
performance status.
 There are two basic versions: the standard BFM
regimen and a more intensive "augmented BFM"
regimen. Both versions include the same induction
therapy that consists
of vincristine, daunorubicin, prednisone,
asparaginase, intrathecal cytarabine, and
intrathecal methotrexate.

 A retrospective single institution study of standard or
augmented BFM in 29 adults (age 19 to 70) with newly
diagnosed ALL reported a CR rate of 93 percent [63].
 At a median follow-up of 6.7 years,
 five-year EFS were 39 and 50 percent for patients who received
standard and augmented BFM, respectively.
 There were two toxic deaths.
 The most common nonhematologic toxicities were infections
(89 percent severe) and sensory neuropathy

 SR defined as
 PGR,( less than 1x109 /L blasts)
 age 1 year to younger than 6 years,
 initial WBC less than 20x109 L, and
 M1 (< 5% blasts) or M2 ( >=5% to < 25% blasts) marrow on day
15, and
 M1 marrow on day 33 (all criteria must be fulfilled)
 Intermediate risk (IR), defined as
 PGR,( less than 1x109 /L blasts)
 age younger than 1 year or age 6 years or older,
 and/or WBC 20x109 /L and
 M1 or M2 marrow on day 15 and M1 marrow on day 33,
 or SR criteria but M3 ( 25% blasts) marrow on day 15 and M1
marrow on day 33;
 HR, defined as
 at least one of the following:
 PPR, (greater than 1x109/L Blasts)
 IR and M3 marrow on day 15,
 M2 or M3 marrow on day 33, t(9;22) (BCR-ABL), or t(4;11) (MLL-
AF4).

Hyper-CVAD
 The combination of
hyperfractionated cyclophosphamide, vincristine, doxorubici
n and dexamethasone (Hyper-CVAD) alternating with high-
dose methotrexate and high-dose cytarabine has also been
used in adults with ALL
 This regimen includes a risk-stratified schedule of central
nervous system prophylaxis with intrathecal methotrexate
and intrathecal cytarabine.
 The dose-intensive phase spans six to seven months and is

 A prospective trial of a Hyper-CVAD-based
regimen
 in 204 patients with newly diagnosed ALL
 median age 39
 91 percent CR rate
 6 percent mortality rate during induction
 Five-year OS was 39 percent.
 Severe, prolonged myelosuppression was
universal.
 Median times to granulocyte and platelet recovery
were 18 and 21 days, respectively.

 Common toxicities included
 infection (55 percent),
 fever of unknown origin (45 percent),
 neurotoxicity (6 percent),
 moderate to severe mucositis (6 percent),
 moderate to severe diarrhea (3 percent),
 ileus (2 percent), and
 disseminated intravascular coagulation (2 percent

 Further follow-up (median of 63 months) of 288 patients with
newly diagnosed ALL treated with this hyper-CVAD-based
regimen reported a
 CR rate of 92 percent and
 five-year OS rates of 38 percent
 Induction mortality varied with patient age being
 2% Vs 15 % for patients <60 or ≥60 years of age, respectively.
 One study using historical controls reported that the addition
of rituximab to the hyper-CVAD regimen resulted in superior
survival rates in younger patients with ALL that expressed
CD20

 There was no benefit for older patients
 For older adults, the doses of the chemotherapy drugs
have been reduced in the mini-hyperCVD regimen, and
the doxorubicin has been eliminated

 GRAALL 2003 regimen — The GRAALL-2003 regimen is
a pediatric-inspired therapy that includes remission
induction with high doses of prednisone, vincristine, and
asparaginase in combination
with daunorubicin, cyclophosphamide, and
intrathecal methotrexate
 A phase II trial of GRAALL 2003 conducted in
 225 adults patients
 median age 31 years
 with Philadelphia chromosome negative ALL reported a
 CR rate of 94 percent

 Severe (grade 3/4) non-hematologic toxicities during
induction included
 liver toxicity (20 percent),
 thromboembolism (4 percent),
 intolerance to asparaginase (2 percent), and
 peripheral neuropathy (1 percent).
 There were 14 deaths during induction due to sepsis
(nine patients), stroke (four patients), and liver failure
(one patient).

 A separate phase II trial evaluated a modified
GRAALL 2003 in 148 adults with lymphoblastic
lymphoma.
 Induction mortality was 3 percent.
 Among the 131 patients with T-lineage LL,
 91 percent achieved a CR
 EFS and OS rates at three years were 63 and 69
percent, respectively.
 Among the 17 patients with B-lineage LL,
 76 percent achieved a CR.
 Survival rates could not be estimated due to the small
numbers of B-lineage LL.

GRAALL 2005 regimen —
 787 evaluable patients (525 B cell and 262 T cell)
with a
 median age of 36.1 years (range, 18 to 59 years)
were
 randomly assigned to receive a
 standard dose of cyclophosphamide or hyperfractionated
cyclophosphamide during first induction and late
intensification,
 GRAALL 2003 chemotherapy backbone.

 With a median follow-up of 5.2 years,
 the five-year rate of EFS and OS rates were 52 percent and
59 percent , respectively.
 Randomization to the hyperfractionated cyclophosphamide
arm did not increase the CR rate or prolong EFS or OS.
 Overall, tolerability of this intensive pediatric-derived
treatment was poor in patients >55 years of age

Post-remission therapy for
Philadelphia chromosome negative
acute lymphoblastic leukemia in adults

 Induction therapy aims to reduce the total body
leukemia cell population from approximately 1012 to
below the cytologically detectable level of about
109 cells.
 It is assumed, however, that a substantial burden of
leukemia cells persists undetected in patients in initial
clinical and morphologic CR (ie, "minimal residual
disease"), leading to relapse within a few weeks or
months if no further therapy were administered.

 The primary aim of post-remission therapy (eg,
consolidation, intensification) is to eradicate this
minimal residual disease.
 There are three basic options for post-remission
therapy (in order of increasing intensity):
 consolidation plus maintenance chemotherapy,
 autologous hematopoietic cell transplantation
(HCT), or
 allogeneic HCT.

 The choice among these for an individual patient
depends upon a number of factors, including:
 Expected rate of relapse with consolidation
chemotherapy alone (influenced strongly by the patient
and tumor characteristics)
 Expected morbidity and mortality associated with
treatment options (as determined by patient
characteristics such as age and comorbidities)
 Salvage (or rescue) therapies available for the treatment
of relapsed disease

CONSOLIDATION AND INTENSIFICATION
 Consolidation chemotherapy –
 Autologous hematopoietic cell transplantation
(HCT)
 Allogeneic HCT

Standard-risk disease
 Consolidation chemotherapy produces four-year
survival rates of 40 to 60 percent
 Common major side effects include pancytopenia,
infection, liver toxicity, and neuropathy.
 Allogeneic HCT results in a lower relapse rate, but
higher rates of treatment-related mortality and
morbidity resulting in similar rates of long-term
survival.

 In contrast, autologous HCT does not appear to
improve on the results seen with consolidation
chemotherapy or allogeneic HCT in this population.
 No randomized trials directly comparing consolidation
chemotherapy with allogeneic HCT
 For most patients with standard-risk ALL in CR1, s the
use of consolidation chemotherapy rather than either
allogeneic or autologous HCT is suggested.

 Consolidation chemotherapy for ALL consists of a
variety of chemotherapy agents with different
mechanisms of action administered in
combinations over several courses at short
intervals that span a total of approximately seven
months.
 The individual drugs used vary by protocol, but
typically include cyclophosphamide, 6-
mercaptopurine, cytarabine, vincristine,
and doxorubicin

 Central nervous system prophylaxis with either
intrathecal chemotherapy or radiation therapy is
incorporated as well.
 The goal is to deliver high doses of these agents
without causing severe cytopenias that lead to
treatment delays.

High-risk disease
 Patients with high-risk disease, do poorly when
treated with consolidation chemotherapy alone after
attainment of a complete remission (CR1);
 rates of 10-year overall survival with this approach are
approximately 10 percent.
 In contrast, treatment with allogeneic HCT provides
an additional GVL effect together with myeloablative
chemotherapy, resulting in superior survival rates of
approximately 45 percent at 10 years.

 For young patients with high-risk ALL in CR1 who have an
HLA-matched donor, allogeneic HCT is recommended
rather than consolidation chemotherapy or autologous HCT
 Unfortunately, many patients achieving a CR are excluded
from HCT due to early relapse, comorbid medical
conditions, or lack of a suitable HLA-matched donor
 For patients with high-risk ALL in CR1 who are not
candidates for allogeneic HCT because of older age or
comorbidities, consolidation chemotherapy is suggested
rather than autologous HCT

Allogeneic transplantation
 When used for young adults with high-risk
disease, allogeneic HCT results in 10-year overall
survival rates of approximately 45 percent.
 For patients >45 years who may not be eligible
for myeloablative conditioning, reduced intensity
conditioning may be an acceptable approach

Allogeneic transplant versus chemotherapy
 The French LALA-87 trial investigated the use of allogeneic
HCT, autologous HCT, or consolidation chemotherapy for
436 patients with ALL in first complete remission (CR1)
 Patients aged 15 to 40 years underwent HLA-typing and
116 had an HLA-identical sibling, 98 of whom underwent a
matched sibling HCT.
 Those without an HLA-identical sibling and patients 40 to 50
years old were randomly assigned to
 either autologous HCT (95 patients) or chemotherapy (96
patients).

 All patients over 50 years were treated with
chemotherapy alone
 In a donor versus no donor comparison of the
transplant-eligible group,
 there was no significant difference in median disease-
free survival (24 versus 22 months) or
 there was no significant difference in overall survival (51
versus 30 months) for those patients with or without
sibling donors

 An international (MRC/ECOG) ALL trial
 randomized trial that compared these same three
consolidation strategies in 1484 adults with ALL in
CR1
 Patients younger than 55 years who had an HLA-
matched sibling donor were assigned to allogeneic
HCT.
 Other patients were randomly assigned to auto-
HCT or chemotherapy for 2.5 years

 Median follow-up is five years
 1031 patients who were younger than 55 years
found that patients with a donor had a significantly
higher five-year overall survival rate (53 versus 45
percent)
 no significance difference in a subset analysis of
the high-risk patients without the Ph chromosome
(41 versus 35 percent)

 This was likely due to a
 higher two-year non-relapse mortality rate among the
high-risk patients with a donor Vs the standard-risk
patients with a donor (36 versus 20 percent).
 On a subset analysis of the 562 standard-risk
patients, patients with a donor
 had a significantly lower relapse rate at 10 years (24
versus 49 percent),
 a higher non-relapse mortality rate at two years (19.5
versus 6.9 percent), and
 a higher overall survival rate (62 versus 52 percent)
when compared with those without a donor.

 Patients randomized to receive chemotherapy
compared to autologous HCT had
 significantly improved rates of five-year event-free
(41 versus 32 percent) and
 significantly improved overall (46 versus 37 percent)
survival

 A 2013 meta-analysis included individualized data
from 2962 patients with Philadelphia
chromosome negative ALL in CR1 enrolled in 13
trials with randomization to allogeneic HCT .
 The identification of a matched sibling donor was
associated with the following outcomes:
 Fewer relapses (odds ratio [OR] 0.58)
 Higher treatment related mortality (OR 2.36)
 Superior overall survival (hazard ratio 0.87)

 For patients classified as having high-risk
disease(white blood cell count at diagnosis
>30,000/microL in B-ALL or >100,000/microL in T-
ALL),
 overall survival was not significantly improved for those
with a matched sibling (hazard ratio 0.90)
 The survival benefit was most apparent in patients
<35 years (HR 0.79;) and was not demonstrated in
patients ≥35 years (HR 1.01).
 This is due to a decreased TRM in patients <35 years
(32 versus 19 percent in those with donors).

 There is clearly more treatment-related mortality as
well as later morbidity after allogeneic HCT than after
chemotherapy alone.
 However, the relapse rate is reduced by allogeneic
transplantation.
 Younger age (<35 years), better transplantation
methods, and availability of an optimal donor may
favor allogeneic HCT in CR1.

BFM 2002
 HSCT in First CR
 OF 846 high risk patients
530 (62.6%) were eligible for HSCT from MSD in
the first CR (CR1).
131 (15.5%) were allografted in 1st CR, 4 to 18
months (median, 7 months) from diagnosis
 For patients who stayed in remission at least
6 months,
 the EFS was 63% ( 5%) for the HSCT group versus
59% ( 3%) for the chemotherapy-only group
(P=.49).

 HSCT was associated with a significantly higher
cumulative incidence of therapy-related mortality
(TRM; 18% v 9%; P =.02),
 but with a trend for lower incidence of relapse
(18% v 29%; P=.09) compared with
chemotherapy

 Immunotherapy — The bispecific
antibody blinatumomab has been approved for
treatment of relapsed CD19+ B-lineage ALL.
 recently evaluated as post-remission therapy for adults
with ALL.
 Similarly, the anti-CD22
immunoconjugate inotuzumab ozogamicin has also
been approved for relapsed or refractory B-lineage
ALL, and
 it too was recently evaluated as post-remission therapy
for adults with ALL.

Phase II BLAST Trial of Blinatumomab in
B-Cell ALL With CR and MRD: Study
Design
 Open-label, international, single-arm phase II study
Adult patients with B-
cell precursor ALL in
hematologic CR with
MRD ≥ 10-3 by
RT-qPCR or flow
cytometry
(N = 116)
Blinatumomab
15 μg/m2 IV daily for up to 4
cycles
(4 wks on, 2 wks off)
Patients could receive
allogeneic HSCT after
cycle 1
Until disease
progression or
unacceptable toxicity;
hematologic RFS
evaluated
at 18 mos
Pretreatment with
corticosteroids required,
HSCT allowed at any time after
cycle 1 .
 Primary endpoint: complete MRD response (10-4) after 1 cycle of
blinatumomab
 Secondary endpoint: hematologic RFS at 18 mos
 Of note, 29% of patients received chemotherapy after blinatumomab

Inotuzumab Ozogamicin + Mini-Hyper-CVD
as Frontline Therapy in Patients > 60 Yrs of
Age
10
0
80
60
40
20
0
Survival
(%)
72
0 12 24 36 48 60
52
(0)
52
(0)
32
(8)
31
(8)
21
(16)
19
(15)
16
(18)
14
(17)
8
(26)
7
(24)
1
(33)
1
(30)
0
(34)
0
(31)
1.
0
0.
8
0.
6
0.
4
0.
2
0
Survival
Probability
Yrs
0 1 2 3 4 5 6 7 8 9 10
Survival in ALL by Age and
Treatment[2] (MDACC: 1983-
2006, N = 565)
48%
9%
Age, Yrs
< 60
≥ 60
≥ 60
Regimen
HCVAD
HCVAD
Pre-
HCVAD
P < .001
Total
409
122
34
Died
200
94
33
20%
Patients at
Risk, n
(Censored)
OS
PFS
PFS
OS
2 Yr (95% CI)
59% (43-72)
66% (50-78)
3 Yr (95% CI)
49% (32-64)
56% (39-79)
Median
35 mos
Not reached
Mos From Start of Treatment
Inotuzumab + Mini-Hyper-
CVD
PFS and OS[1]

CNS PROPHYLAXIS
 ALL has a high risk of CNS involvement with some studies
reporting rates as high as 78 percent at some point in the
disease course in patients not given CNS prophylaxis
 This rate appears to decrease to less than 20 percent when
CNS prophylaxis is routinely administered.
 Less than 10 percent of patients will have CNS involvement
at the time of diagnosis.

CNS PROPHYLAXIS
CNS-Directed Therapy
 Standard treatment options for CNS-directed
therapy include:
 1. Intrathecal chemotherapy.
 2. CNS-directed systemic chemotherapy.
 3. Cranial radiation therapy.

Intrathecal Chemotherapy:
 Usually started at the beginning of induction, intensified during
consolidation and, in many protocols, continued throughout the
maintenance phase.
Intrathecal chemotherapy typically consists of one of the following:
 1. Methotrexate alone.
 2. Methotrexate with cytarabine and hydrocortisone (triple intrathecal
chemotherapy).
 Unlike intrathecal cytarabine, intrathecal methotrexate has a significant
systemic effect, which may contribute to prevention of marrow
relapse.

Triple intrathecal chemotherapy vs. intrathecal methotrexate
Studies found:
• No differences in the cumulative incidence of isolated bone marrow
relapse, isolated CNS relapse, or combined bone marrow and CNS
relapse between the two arms.
• There were no significant differences in neurologic toxicities

 CNS-Directed Systemic Chemotherapy
1. Dexamethasone.
2. L-asparaginase (does not penetrate into CSF itself, but leads to CSF
asparagine depletion).
3. High-dose methotrexate with leucovorin rescue.
4. Escalating dose intravenous (IV) methotrexate without leucovorin rescue.
In a randomized CCG study :
Oral dexamethasone was associated with a 50% decrease in the rate of CNS
relapse compared with oral prednisone.

 Cranial radiation therapy
There is a growing consensus that cranial radiation therapy may not be
necessary for most of these patients.
Indications for cranial radiation therapy on some treatment regimens :
1. T-cell phenotype and high initial WBC count.
2. Patients with high-risk B-ALL and extremely high presenting leukocyte
counts and/or adverse cytogenetic abnormalities

CNS Therapy for Patients With CNS3 Disease at
Diagnosis:
• Therapy for ALL patients with clinically evident CNS disease (CNS3) at
diagnosis typically includes:
intrathecal chemotherapy and cranial radiation therapy (usual dose is 18 Gy).
• meta-analysis of aggregated data from more than 16,000 patients-In
subgroup analyses of high-risk subsets only those with CNS3 status
benefit from cranial radiation therapy.
-significantly lower rate of CNS relapses (isolated/any) in irradiated
patients, however, OS was similar with or without the use of radiation therapy.

MAINTENANCE THERAPY
 Remission maintenance therapy is a standard component of
the management of ALL and is given for two to three years
after consolidation therapy.
 In general, maintenance therapy is not used after allogeneic
HCT.
 Most standard maintenance regimens consist of daily 6-
mercaptopurine, weekly methotrexate and in regimens such
as Hyper CVAD monthly pulses of vincristine and prednisone
are also given(ie, POMP)

 In many protocols, intrathecal chemotherapy for CNS
sanctuary therapy is continued during maintenance therapy.
 Trials omitting or shortening maintenance therapy appear to
produce inferior results than those obtained with maintenance.
 In addition, longer maintenance may not improve on results
seen with two years of maintenance

 Two prospective studies that omitted maintenance
treatment following the completion of consolidation
therapy are notable for short disease-free survival
times when compared with historical controls
 CALGB study 8513
 ECOG studies 2483 and 3486

 In CALGB study 8513, in which treatment was
completed after 29 weeks, the median remission
duration was
 only 11 months Vs 21 months in CALGB study 8011
(three years of therapy were administered)
 ECOG studies 2483 and 3486
 induction followed by intensive 12-month consolidation,
but no maintenance therapy.
 The median disease-free survivals were only 9 and 11
months, respectively

MTX- 20 mg/m2 vs 40mg/m2:
• In the COG AALL093 trialrandomly assigned to receive
weekly oral methotrexate during maintenance at one of two
starting doses: 20 mg/m (standard) or 40 mg/m.
• There was no significant difference in 5-year DFS from
the start of maintenance therapy between the two
treatment arms (5-year DFS rate, 95.1% (standard dose)
vs. 94.2% , P = .92).
 Indicating no advantage for the higher dose of oral methotrexate.

 Trimethoprim-
sulfamethoxazole, dapsone, pentamidine,
or atovaquone prophylaxis may be used to
prevent Pneumocystis jirovecii (P. carinii)
pneumonia
 Patients are followed after the completion of
maintenance therapy for signs and symptoms of
relapsed disease or late effects of treatment.

MANAGEMENT OF
PHILADELPHIA POSITIVE ALL

 Ph-positive ALL is rare in children with ALL,
occurring in only approximately 3% of pediatric
cases compared with 25% of adult cases
 The frequency of Ph-positive ALL among AYA
patients ranges from 5% to 25% and increases
with age
 Historically, children and adolescents with Ph-
positive disease had a poorer prognosis
compared with patients with Ph-negative B-ALL.
 However, recent improvements in the treatment
options are closing this gap.

 Real-time quantitative PCR (RQ-PCR) for BCR-
ABL1 transcript should be performed to establish a
baseline value for monitoring MRD.
 Mutation analysis of BCR-ABL1 is not routinely
performed at the time of initiation of induction
therapy.

REMISSION INDUCTION THERAPY
 All remission induction regimens for Ph+ ALL
must include:
 BCR-ABL1 tyrosine kinase inhibitor (TKI).
plus
 A glucocorticoid or chemotherapy.
 In addition, all induction regimens must include
central nervous system (CNS) management that
is determined by the chosen induction regimen

Evidence for the role of TKI
 For remission induction therapy of Ph+ ALL, a
regimen that includes a TKI is recommended
rather than a regimen that does not include a TKI,
 No randomized trials have directly compared
specific remission induction regimens with or
without a TKI.

 However, inclusion of a TKI in induction therapy is
associated with markedly superior outcomes and
little incremental toxicity, based on numerous
prospective and retrospective studies

Choice of TKI
 No specific BCR-ABL1 TKI is optimal for all patients
with Ph+ ALL
 Dasatinib is favoured because it has an established
track record in prospective studies and may have
some CNS penetration, it is effective against
some BCR-ABL1 mutations that do not respond
to imatinib , and it is generally well-tolerated.

 It acceptable to treat with a different TKI for the
following reasons:
 Contraindication –
 For patients with a pleural effusion, pulmonary
hypertension, cardiac dysrhythmias, or qualitative
platelet disorders, generally should treat
with imatinib, nilotinib, or ponatinib.

 Individual TKIs have not been compared head-to-
head in Ph+ ALL.
 A meta-analysis analysis showed superiority of
ponatinib-based regimens over regimens
containing first- or second-generation TKIs,
but ponatinib is associated with substantial
cardiovascular toxicity

Dasatinib
 Dasatinib is a multitargeted TKI that has been
widely used for Ph+ ALL.
 Treatment is associated with cytopenias, pleural
effusions/fluid retention, QTc prolongation, and
bleeding.
 Dasatinib should be avoided in patients with a
history of bleeding, pleural effusion, or heart
failure.

 Administration – Dasatinib is administered as 140 mg by
mouth daily, with or without food;
 Patients should be screened by electrocardiogram (EKG)
for QTc interval at baseline,
 Hypokalemia or hypomagnesemia should be corrected
before administration of dasatinib.
 No initial dose adjustment is required for patients with liver
or kidney impairment.

 Adverse effects – Most adverse effects (AE) are
mild and self-limited .
 Patients may experience QTc prolongation, fluid
retention (grade ≥3 AEs in approximately 4
percent), exacerbation of congestive heart failure,
or significant bleeding.

Outcomes –
 In combination with chemotherapy, dasatinib is generally
associated with >90 percent CR.
 Remission induction with dasatinib plus a glucocorticoid in
63 patients achieved 98 percent CR and 29 percent
molecular complete remission (molCR)
 High rates of CR and robust molecular response have also
been reported for dasatinib combined with low-intensity
chemotherapy , high-intensity chemotherapy , and various
chemotherapy regimens

 Dasatinib is approved for treatment of Ph+ ALL by
the US FDA.
 It is approved by the EMA for Ph+ ALL with
resistance or intolerance to prior therapy,
including imatinib .

 Imatinib
 Compared with second and third generation TKIs,
the response to imatinib is generally not as fast or
deep, and it is less effective against various BCR-
ABL1 kinase domain mutations.
 Imatinib is associated with cytopenias and
edema, and it causes substantial fluid retention in
some patients;
 generally avoided in patients with a history of
significant fluid retention or nausea

 Administration – Initial treatment is
with imatinib 400 mg once daily with a meal and a
large glass of water
 The initial dose of imatinib should be adjusted for
liver or renal impairment,
 Concurrent use of strong CYP3A4 inducers
should be avoided.

 Adverse effects – Most AEs are mild and self-
limited
 The most common AEs are cytopenias, edema,
nausea, diarrhea, rash, and muscle cramps; grade
≥3 AEs are reported in ≤5 percent of patients.

Outcomes
 In a study of 80 patients, treatment with imatinib plus
multiagent chemotherapy was associated with
 96 percent CR, with approximately 70 percent of
patients achieving molCR;
 One -year OS and event-free survival (EFS) were 76
and 60 percent, respectively
 Emergence of imatinib-resistant clones due to
acquired mutations in BCR-ABL1 is common.

Nilotinib
 Nilotinib is an acceptable TKI for patients with a
contraindication or intolerance to dasatinib (eg,
pleural effusion, pulmonary hypertension, cardiac
dysrhythmias) or imatinib (eg, substantial edema).
 Nilotinib is the only TKI that must be taken twice
daily and without food. It is administered 300 mg
twice daily with water;

 Patients should avoid food ≥2 hours before and ≥1
hour after taking each dose.
 Patients should be screened by EKG for QTc interval
at baseline, and potassium and magnesium levels
should be corrected
 Nilotinib is associated with cytopenias, hepatotoxicity,
QTc prolongation, pancreatitis, and long-term
cardiovascular complications

Chemotherapy versus a
glucocorticoid
along with TKI
 For remission induction therapy of Ph+ ALL,
 either a TKI plus a glucocorticoid or a TKI plus
chemotherapy (which typically also includes a
glucocorticoid) --> acceptable treatments
Favoring chemotherapy
 Some experts favor a TKI plus chemotherapy
because of the long experience with this
approach and the potential to achieve a robust
molecular response

 Some studies reported that a deeper molecular
response was associated with improved outcomes in
patients treated with intensive chemotherapy, but
this benefit may be offset by substantial morbidity
and some early treatment-related deaths

 Choice of chemotherapy regimen
 Low-intensity
 Moderate intensity
 High intensity

Low-intensity
 low-intensity regimens to be those that include
only a single nonmyelosuppressive
chemotherapy agent (eg, vincristine ) plus a
glucocorticoid.
 EWALL-PH-01 is an example of a low-intensity
regimen:

 EWALL-PH-01 was associated with 96 percent CR
and 65 percent MMolR .
 Rates of five-year OS and relapse-free survival
(RFS) were 36 and 28 percent, respectively;
 In the EWALL-PH-02 study, nilotinib (400 mg twice
daily) was incorporated into the EWALL-PH-01
regimen;
 97 percent CR and 29 percent achieved molCR during
the consolidation phase

Moderate-intensity
 Suitable for medically-fit patients and for selected
patients who are medically-unfit, but not frail.
 CALGB 10701
 Mini-hyperCVD

RESULTS
 TOTAL : 64 patients
 Median follow up : 4 years
 median OS: 45 month,
 three-year OS: 55 percent
 three-year disease-free survival (DFS):43%

 The mini-hyper-CVD (cycles 1, 3, 5, 7) comprised
cyclophosphamide (150 mg/m2 every 12 h on
days 1-3), vincristine (2 mg flat dose on days 1 and
8), and dexamethasone (20 mg on days 1-4 and days
11-14) without anthracycline.
 Cycles 2, 4, 6, 8 comprised methotrexate (250
mg/m2 on day 1) and cytarabine (0.5 g/m2 given every
12 h on days 2 and 3)
 Similar outcomes comparable to other moderate
intensity regimens

High-intensity
 High-intensity chemotherapy regimens are only
suitable for medically-fit patients.
 Can achieve a robust molecular response, but
they are associated with substantial treatment-
related morbidity and possible mortality

Favoring glucocorticoid
 Other studies favor a TKI plus a glucocorticoid
because this can achieve high rates of CR with
little toxicity, thereby enabling post-remission
management with little morbidity and mortality.

Administration – An example of an induction regimen
consisting of glucocorticoid along with TKI is two 28-
day cycles of:
 Dexamethasone (10 mg/m2/day orally or IV on days
1 to 7)
plus
 Dasatinib 140 mg orally daily

POST REMISSION THERAPY IN Philadelphia
positive ALL
Post-remission therapy comprises:
 Consolidation therapy – Intensive treatment that
follows soon after achievement of hematologic
CR.
 Maintenance therapy – Prolonged lower-intensity
treatment that includes a BCR-ABL1 TKI, with or
without chemotherapy.

 Indications
 For most patients with Ph+ ALL, consolidation
therapy is suggested , rather than maintenance
therapy alone or observation only
 Consolidation therapy offers the greatest
likelihood of long-term survival for patients with
Ph+ ALL, but is associated with adverse effects
that vary with the chosen approach.

 No randomized trials have compared
consolidation therapy versus maintenance
therapy alone or observation only
 it is difficult to compare different studies because
of various selection criteria and measures of
outcomes.

 Most studies with maintenance therapy alone
involved frail or less-fit patients or were from the
pre-tyrosine kinase inhibitor (TKI) era.
 Observation alone is associated with relapse
within months in virtually all patients. Selection of
consolidation therapy is discussed below

Selected patients with undetectable
measurable residual disease (MRD):
 Transplant-eligible
 Not a transplant candidate

 Transplant-eligible – For patients with
undetectable MRD who are candidates for
allogeneic hematopoietic cell transplantation
(HCT),
 Not a transplant candidate – For patients with
undetectable MRD who are not candidates for
allogeneic HCT,
--> proceed to consolidation chemotherapy or
corticosteroids plus TKI or only TKI

 Frail patients – For frail patients, can directly to
maintenance therapy because the toxicity of
consolidation therapy in this population may
outweigh the benefits

Choices for transplant candidates
 Preference for allogeneic HCT
 For most patients with Ph+ ALL who are eligible for
transplantation, consolidation with allogeneic HCT
rather than autologous HCT, chemotherapy, or
immunotherapy is suggested
 Allogeneic HCT is associated with the most favorable
long-term outcomes for Ph+ ALL, but this benefit must
be weighed against substantial toxicity and treatment-
related mortality (TRM),
 which vary with patient age and transplantation
technique

 Studies that compared allogeneic HCT with other
approaches generally used "genetic
randomization," in which allogeneic HCT is
offered to patients with a human leukocyte
antigen (HLA)-matched donor, while other
patients received either autologous HCT or
chemotherapy.

Pretransplant management by
MRD status
 Detectable MRD
 MRD not detected (molCR)

 Detectable MRD
 Maximizing the depth of response prior to
allogeneic HCTis preferred , because deeper
molecular responses are associated with more
favorable outcomes.
 For patients with detectable MRD (eg,
<MR4.5; BCR/ABL1 >10-4.5), treatment to
deepen the response prior to transplantation is
preferred

 Treatments that can enhance the molecular
response in patients with persistent MRD include:
 Blinatumomab is available:
 Treat with blinatumomab to achieve undetectable
MRD (ie, ≥MR4.5) and then proceed to allogeneic
HCT.
 If one or two cycles of blinatumomab does not
achieve undetectable MRD, further treatment is
unlikely to provide additional benefit

Blinatumomab is not available:
 Patient is receiving imatinib:
 For patients who received imatinib during remission
induction therapy, treat for one to two months with
a second-generation TKI (eg, dasatinib) or ponatinib
with multiagent chemotherapy/corticosteroids -->
allogenic HCT
 Patient is not receiving imatinib:
 For patients who were treated with a second- or
third-generation TKI during remission induction
therapy, treat with multiagent chemotherapy along
with the same 2nd or 3rd generation TKI before
proceeding to allogeneic HCT

MRD not detected (molCR)
 For patients with a complete molecular CR
(molCR; ie, ≥MR4.5; BCR/ABL1 ≤10-4.5), --->
proceed directly to HCT
 Donor source — An HLA-matched related donor
or matched unrelated donor is preferred
 Conditioning regimen — Myeloablative
conditioning (MAC) and reduced intensity
conditioning (RIC) are associated with similar
outcomes for allogeneic HCT in Ph+ ALL

 Resumption of TKI — The TKI is generally
withheld at the time of HCT.
 Resume the TKI as soon as possible after
recovery of blood counts, recognizing that
gastrointestinal or hematopoietic toxicity or drug
interactions may delay initiation of TKI
 No studies have defined an optimal period for
withholding the TKI, but the interruption is
generally 30 to 60 days.

Not a transplant candidate — For patients with
Ph+ ALL who are not candidates for allogeneic
HCT, the following options can be considered for
consolidation therapy:
 Chemotherapy plus a TKI.
 Immunotherapy.
 Autologous HCT

Choices for HCT-ineligible
patients
MRD detected in HCT-ineligible patients
 For patients who have detectable MRD (ie,
<MR4.5; BCR-ABL1 >10-4.5), treat
with blinatumomab (two to five cycles), where
available, followed by maintenance therapy.
 The TKI should be withheld during
immunotherapy to reduce the risk of cytopenias
and it should be resumed upon initiation of
maintenance therapy.
 If blinatumomab is not available, treat with a TKI
plus combination chemotherapy followed by
maintenance therapy

 MolCR in HCT-ineligible patients — For patients
with undetectable MRD (molCR), we proceed to
combination chemotherapy or corticosteroids plus
TKI or maintenance therapy.
 Blinatumomab is not approved for treatment of
molCR
 Some experts offer autologous HCT in this setting.
 No studies have compared outcomes and toxicity
with these strategies and the preferred approach
differs between centers.

 Chemotherapy plus a TKI: An acceptable option
for patients with Ph+ ALL who are medically
ineligible for allogeneic HCT
 No protocol for a TKI plus combination
chemotherapy has proven to be superior
 No randomized trials have compared a TKI plus
combination chemotherapy versus allogeneic
HCT, autologous HCT, or immunotherapy

 A prospective study of 71 adults (median age 69
years, most of whom had high comorbidity scores)
reported 36 percent OS at five years in patients who
were treated with dasatinib plus
asparaginase, methotrexate,
and cytarabine consolidation for six months [19].
 Favorable performance status and achievement of a
deep molecular response during consolidation were
associated with prolonged RFS.

 Immunotherapy — Consolidation
with blinatumomab (bispecific anti-CD3 and anti-CD19
antibody) is a promising approach and enables
chemotherapy-free treatment of Ph+ ALL.
 Blinatumomab is approved by the US FDA for patients with
detectable MRD in first CR.
 A phase 2 study of 63 patients that used chemotherapy-
free induction therapy (dexamethasone plus dasatinib) and
consolidation therapy (two to five cycles of blinatumomab)
 reported 95 percent OS and
 88 percent disease-free survival (DFS),
 with median follow-up of 18 months

 At the end of the second cycle of blinatumomab, 60
percent of patients had achieved molCR.
 There were 21 grade ≥3 adverse events
 primarily neutropenia or
 cytomegalovirus reactivation or infection.
 BCR-ABL1 mutations were detected in six patients
who had increasing MRD during induction therapy, but
all clones with mutated BCR-ABL1 were cleared
by blinatumomab.
.

 Relapses occurred in 8 percent of patients and a
total of 24 patients received allogeneic HCT
 There was one death related to transplantation

 Autologous HCT — Autologous HCT has a
limited role for consolidation therapy in Ph+ ALL.
 Generally limited to patients with undetectable
MRD who are not candidates for allogeneic HCT.
 Can achieve long-term deep molecular
remissions in some patients, but it is not yet
clear whether it can routinely cure Ph+ ALL.

 For patients who achieve MMolR (>MR3; BCR-
ABL1 <10-3) after induction therapy, autologous HCT
can achieve outcomes that are comparable to
allogeneic HCT
 A prospective study from the European Group for
Blood and Marrow Transplantation (EBMT) reported
that at three years, autologous HCT was associated
with
 57 percent OS,
 52 percent leukemia-free survival,
 45 percent relapse rate, and
 3 percent NRM .

MAINTENANCE THERAPY
 maintenance therapy should be given to all patients,
regardless of the type of consolidation therapy (eg,
transplantation, chemotherapy, immunotherapy, or no
consolidation because of frailty) and level of
measurable residual disease (MRD),

 The duration of treatment may be influenced by the level
of MRD:
 For >MR4 (ie, BCR-ABL1 <10-4) :
 Treat for at least two years.
 For patients who have undergone allogeneic HCT, some
experts treat for one to two years after transplantation
 For ≤MR4 (ie, BCR-ABL1 ≥10-4):
 continue the TKI indefinitely.
 If MRD subsequently declines to >MR4 in two successive
examinations, treat for at least one year longer (minimum
two years total).

Outcomes
After HCT:
 A systematic review of 17 studies reported that
TKI maintenance therapy after allogeneic HCT
was associated with improved overall survival
(OS)
 compared with imatinib, second-generation TKIs
(eg, dasatinib) were associated with better OS,
especially in patients with MRD-positive status

 In a multicenter phase 3 trial,
 55 patients underwent allogeneic HCT
 randomly assigned to receive maintenance imatinib
for one year versus starting imatinib only at the time
of MRD detection
 After median follow-up of 30 months, there was
no difference
 in estimated five-year OS (77 percent),
 sustained complete remission (CR; 83 percent), or
 disease-free survival (DFS; 69 percent).

 However, patients who received maintenance
imatinib were:
 more likely to remain MRD negative at four years
(46 versus 27 percent, respectively) and
 had a longer median duration of sustained MRD
negativity (27 versus 7 months)

 TKI maintenance may even be clinically useful
after allogeneic HCT in patients who were MRD
negative prior to transplantation.
 TKI maintenance was associated with improved
progression-free survival

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