International collaborative treatment protocol for infants under one year with KMT2A-rearranged acute lymphoblastic leukemia or mixed phenotype acute leukemia

Infant acute lymphoblastic leukemia (ALL) is a rare disease and comprises about
4% of childhood ALL. Whereas the outcome of older children with ALL has
improved to >90% event-free survival (EFS), infants with ALL have a poor
prognosis.
Infant ALL is characterized by a high frequency (~75%) of abnormalities in the
chromosome 11q23 that affect the histone lysine methyltransferase 2A (KMT2A)
gene, formerly known as mixed lineage leukemia (MLL) gene. KMT2A-rearrangements
(KMT2A-r) occur in only 2% of older children with ALL. KMT2A-r is associated
with poor outcome.
nfant ALL has a very immature CD19-positive B-cell phenotype (pro-B ALL)
without CD10 expression, and a high tumor load at diagnosis. Infant ALL cells
are more resistant to chemotherapy than ALL cells of older children, but are
sensitive in vitro to cytarabine. Therefore the Interfant treatment protocol
contains more cytarabine than a standard ALL regimen for older children.

Unfortunately, treatment outcome has not significantly improved in the last few
decades. This supports the need for improvement of upfront treatment with
innovative strategies directed against novel targets.


The Interfant-21 protocol will implement several major changes to the
Interfant-06 backbone (see section study design)

This study has been transitioned to CTIS with ID 2022-502503-30-00 check the CTIS register for the current data.

The primary objective is to improve the outcome (in terms of event-free
survival (EFS) as the primary endpoint) of newly diagnosed KMT2A-rearranged
(KMT2A-r) infant acute lymphoblastic leukemia (ALL) compared with the
historical results of the Interfant06 protocol.

The secondary objectives are:
1. To estimate overall survival (OS) and compare it with corresponding
historical results of the Interfant-06 protocol, in the whole study and by risk
group.
2. To determine outcome (in terms of secondary endpoint 2) according to risk
group and com-pare it with corresponding historical results of the Interfant-06
protocol.
3. To determined outcome (in terms of secondary endpoint 3) taking into account
the protocol-specific definition of resistance.
4. To assess the response to different treatment phases in term of minimal
residual disease (MRD) response.
5. To evaluate the incidence of CD19 negative relapses
6. To evaluate the incidence of myeloid lineage switches
7. To describe the toxicity associated to each treatment phase.
8. To describe long term cardiotoxicity
9. To evaluate survival after relapse, overall and by risk group

International multicenter open-label non-randomized phase 3 clinical trial
conducted in the Interfant network. This protocol is a master protocol which
will be implemented in all participating countries and sites, with a number of
sub-studies that will only be performed in a restricted number of countries and
sites (based on feasibility and interest). This will be documented in a
sub-study manual, and participation in these studies will be clearly documented
in the submission package in each country/site. The objectives and design of
the sub-studies are provided in the sub-study protocols.

The Interfant-21 protocol will implement several major changes to the
Interfant-06 backbone, listed below, and in more detail in the following
paragraphs:
• Less stringent adaptation of age-based dose reduction guidelines.
• Allocation to lymphoid or myeloid consolidation therapy, based upon EOI MRD
in MR patients.
• One cycle of blinatumomab following induction in all patients.
• A second cycle of blinatumomab will replace MARMA in MR patients with a good
response af-ter the first cycle of blinatumomab.
• All HR patients and MR patients with insufficient MRD response will be
eligible for for allogene-ic hematopoitetic stem cell transplantation (HSCT) as
soon as they have become MRD nega-tive or at least < 0.01%.
• HR patients and MR patients with insufficient MRD response after will be
eligible for experi-mental therapy, such as CAR T-cell therapy, which cab be on
a separate trial, as a bridge to HSCT.


The Interfant-21 study will not include a randomization because of the rarity
of the disease and the unsatisfactory stable outcome of treatment without
blinatumomab in the Interfant-99 and Interfant-06.

1 or 2 cycles blinatumomab

Whereas the outcome of older children with ALL improved > 85%, infants with
KMT2A-r ALL have an EFS of less than 40%, hence there is clear medical need in
this specific population.

1) Risk and benefits of addition blinatumomab

Within the Interfant consortium a phase 2 clinical trial with blinatumomab was
performed, in which blinatumomab was given after induction. The results showed
the same favorable safety profile and response, as in adults and in older
children (vdSluis #361 ASH2021). The 1years EFS was 90.0%(SE 5.5) , which was
remarkable better than Interant-06 (1-year EFS 54.8%(SE 2.3) ). Two randomized
phase 3 trials in high-risk relapsed pediatric ALL also shown the superiority
of one or two cycles of blinatumomab in consolidation when randomized against
chemotherapy, due to both higher disease clearance as well as reduced toxicity.
Therefore blinatumomab will be added to the Interfant-06 back-bone for all
patients.
To potentially further increase efficacy and decrease treatment related
toxicity, medium risk patients with a good response to one cycle of
blinatumomab will receive a second cycle of blinatumomab re-placing the
conventional chemotherapy block MARMA. There may be a higher relapse risk if
intensity of conventional chemotherapy is decreased, but this will be mitigated
by including only those patients who have obtained a good response to the first
cycle of blinatumomab. Moreover, this strategy is also based on the data in
older children with relapsed ALL as referenced above. Outcome will be monitored
by the DSMC to alert the Interfant Study Team in case of any evidence of
deviation from the historical results of Interfant06. Stopping guidelines are
included in the study, based on the number of events to further mitigate this
risk.
Taken together, we anticipate that the addition of blinatumomab will benefit
patients and outweighs the risk of treatment with an investigational agent

2) Risk and benefits of other changes compared to Interfant-06.

a. Less stringent adaptation of age-dependent drug reduction
Compared to the former Interfant-06 protocol, infants will get less stringent
adaptation of age-dependent drug reduction. Thus all infants will receive
higher doses of chemotherapeutic drugs compared to Interfant-06. For decades
Japanese trials (MLL-96 and MLL-10) have used less stringent adaptation of
age-dependent drug reduction and in these trials not more treatment related
mortality was reported with this approach. However higher molecular remission
rates at EOI were achieved and higher EFS was observed.

b. Allocation to myeloid consolidation therapy based on high EOI MRD in medium
risk patients
Patients with high EOI MRD will receive more intensive, myeloid style,
consolidation therapy, which is associated with more treatment related toxicity
and mortality (TRM 4.7%, versus 0% in lymphoid style consolidation phase).
However the survival of patients with high EOI MRD was improved by >20% in
Interant-06 (6-y DFS 45.9% with myeloid style consolidation versus 23.2% with
lymphoid style consolidation) in patients with high EOI MRD. So the risk of
higher toxicity and TRM is accepted in a sub-group of patients with very poor
outcome, to increase survival.

c. Broader and earlier eligibility for HSCT
All HR patient and MR with insufficient MRD response will be eligible for HSCT
as soon as they have become MRD negative or at least < 0.01%. In Interfant-06
approximately 50% of HR patients had an event before the scheduled HSCT, of
which 41% due refractory disease or relapse. Therefore HR and eligible MR
patients will be eligible for HSCT as soon as they have become MRD < 0.01% to
avoid relapse before HSCT. TRM of HSCT was approximately 14.4% in Interfant-06
(JCO 2019 Pieters), however in recent years the TRM of HSCT has decreased to
approximately 5% (ref Pieters, JCO 2019). Therefore, the benefit of HSCT to
avoid a relapse seems to outweigh the risks of HSCT.

d. Experimental targeted therapies in an investigation window
High-risk (HR) patients and medium risk patients with insufficient MRD response
after induction and blinatumomab have very poor outcomes with conventional
chemotherapy, therefore these patients will be eligible for experimental
therapy in separate trials in an investigational window, as a bridge to HSCT.
The risk and benefits of these trials will be given in the protocols of these
trials.