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Dual T315I mutation F359I mutation positive pediatric CML lymphoid blast crisis

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9 months 2 weeks ago #1902 by Niharendu
7 year old boy , diagnosed as CML Chronic Phase (bone marrow studies not performed upfront) in March 2022.
Progressed to lymphoid blast crisis in 3 months (June 2022).
Dual mutations T315I mutation (C>T) and p.F359I mutation (T>A) detected.
Had ALL induction (3 drugs , without anthracycline) + Dasatinib, end of induction MRD 0.83%;
also advised allogeneic HSCT. Due to financial constraints, family refused and hence,
the child was offered life- prolonging oral metronomic therapy (6 mercaptopurine/ Etoposide) , Dasatinib and monthly intrathecal therapy.
The Dasatinib had been stopped later.


The family has approached us (different to the primary centre) for second opinion and another go with curative intent.
He has had clinical progression with lymphadenopathy and cytopenias, some disease control with Vincristine + Dexamethasone pulse.
CNS positive with lymphoid blasts in CSF and 10% lymphoid blasts in the haemodilute bone marrow post-pulse.

Q 1. What are the suggested curative therapeutic options?
Q2. With the possible parial resistance of F359I mutated disease to Ponatinib ,
is dual TKI therapy (Dasatinib + Ponatinib) an option , toxicity being a significant concern.
Wil Ponatinib + Asciminib be a potential therapeutic option,
in which case what is the recommended dose for Asciminib in Paediatrics (His Height: 120 cms Weight: 17.9 kg BSA: 0.77 sq m)?
I understand that Trials are underway and would defer to the expert opinion, should Asciminib be an option
  • Meinolf Suttorp
  • Meinolf Suttorp's Avatar
9 months 1 day ago - 9 months 1 day ago #1907 by Meinolf Suttorp
My answer to Q1:

There is no curative approach aside from SCT to be performed at least in partial cytogenetic REMISSION.

My answer to Q2:

I have no experience with the combination of Pona + Dasa and would also be afraid of toxicity.
Pona +Asci might be an option if the latter drug is available.

Trials with escalating doses of Asci in children are recruiting. Please contact Nobuko Hijiya for details.

Most importantly from my view -also as a palliative approach- the CNS involvement must be treated aggressively. Lymphoid blast CNS infiltration can cause extremely painful headache. Triple intrathecal therapy twice weekly until the CNS fluid is free from blasts and thereafter every 2 weeks is my recommendation.

Anyway, I assume without SCT the child will be lost.
Last edit: 9 months 1 day ago by arlene.
  • Nobuko Hijiya
  • Nobuko Hijiya's Avatar
9 months 18 hours ago - 9 months 17 hours ago #1908 by Nobuko Hijiya
I am sorry to hear about the difficult case. I agree BMT is needed. In terms of the asciminib in children, as you said, there is an ongoing Phase I/II pediatric study. Study to Determine the Dose and Safety of Asciminib in Pediatric Patients With Chronic Myeloid Leukemia - Full Text View - clinicaltrials.gov/ct2/show/NCT04925479

In this, the dose is 1.3 mg/kg by a pediatric formulation, which is available only on the study, but please know that we do not have the PK data yet. There are some ongoing studies of asciminib + ATP-competitive TKIs (imatinib, dasatinib, nilotinib) for adult patients, but I am not aware of combination with ponatinib. In terms of ponatinib, there are also ongoing pediatric studies and the dose to be determined, but we have published a case series of ponatinib in children pubmed.ncbi.nlm.nih.gov/31975387/
Last edit: 9 months 17 hours ago by arlene.
  • Giuseppe Saglio
  • Giuseppe Saglio's Avatar
8 months 3 weeks ago - 8 months 3 weeks ago #1911 by Giuseppe Saglio
This is an extremely serious situation and the curative chances are very limited even after an alloBMT and almost absent without a transplantation or CAR-T cell therapy approach.

I think that it is important to know if we are in presence of two mutations in two different subclones or if we are in presence of compound mutations within the same clone. In the latter case the use of a single TKI is not effective and the only possibility is to combine ponatinib and asciminib. Due the dramatic situation I would not care so much about toxicity and, if the body weight is approximately 20 Kg, I would use ponatinib at least at 15 mg and Asciminib at 40-60 mg per day.

If there is an initial response and the % of the blast decreases I would also add blinatumomab as for R/R ALL cases (see scheme in Blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia: results of the RIALTO trial, Franco Locatelli, et al- Blood Cancer Journal volume 10, Article number: 77 (2020) and some intratechal chemo. However, even in case of a good response, I do not think that this situation could last long in absence of a subsequent alloBMT.
Last edit: 8 months 3 weeks ago by arlene.
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8 months 3 weeks ago #1914 by arlene
Nothing further to add to the wisdom of my colleagues. Transplant is the only curative approach in this setting. Agree that aggressive therapy will be needed prior to transplant, esp CNS. Will need post-transplant TKI.


ORIGINAL CASE
Dual T315I mutation F359I mutation positive pediatric CML lymphoid blast crisis
7 year old boy, diagnosed as CML Chronic Phase (bone marrow studies not performed upfront) in March 2022.
Progressed to lymphoid blast crisis in 3 months (June 2022).
Dual mutations T315I mutation (C>T) and p.F359I mutation (T>A) detected.
Had ALL induction (3 drugs , without anthracycline) + Dasatinib, end of induction MRD 0.83%;
also advised allogeneic HSCT. Due to financial constraints, family refused and hence,
the child was offered life- prolonging oral metronomic therapy (6 mercaptopurine/ Etoposide) , Dasatinib and monthly intrathecal therapy.
The Dasatinib had been stopped later.


The family has approached us (different to the primary centre) for second opinion and another go with curative intent.
He has had clinical progression with lymphadenopathy and cytopenias, some disease control with Vincristine + Dexamethasone pulse.
CNS positive with lymphoid blasts in CSF and 10% lymphoid blasts in the haemodilute bone marrow post-pulse.

Q 1. What are the suggested curative therapeutic options?
Q2. With the possible parial resistance of F359I mutated disease to Ponatinib ,
is dual TKI therapy (Dasatinib + Ponatinib) an option , toxicity being a significant concern.
Wil Ponatinib + Asciminib be a potential therapeutic option,
in which case what is the recommended dose for Asciminib in Paediatrics (His Height: 120 cms Weight: 17.9 kg BSA: 0.77 sq m)?
I understand that Trials are underway and would defer to the expert opinion, should Asciminib be an option.

ORIGINAL RESPONSE: Professor Meinolf Suttorp
My answer to Q1:
There is no curative approach aside from SCT to be performed at least in partial cytogenetic REMISSION.
My answer to Q2:
I have no experience with the combination of Pona + Dasa and would also be afraid of toxicity.
Pona +Asci might be an option if the latter drug is available.
Trials with escalating doses of Asci in children are recruiting. Please contact Nobuko Hijiya for details.
Most importantly from my view -also as a palliative approach- the CNS involvement must be treated aggressively. Lymphoid blast CNS infiltration can cause extremely painful headache. Triple intrathecal therapy twice weekly until the CNS fluid is free from blasts and thereafter every 2 weeks is my recommendation.
Anyway, I assume without SCT the child will be lost.

FURTHER RESPONSE: Nobuko Hijiya

I am sorry to hear about the difficult case. I agree BMT is needed. In terms of the asciminib in children, as you said, there is an ongoing Phase I/II pediatric study. Study to Determine the Dose and Safety of Asciminib in Pediatric Patients With Chronic Myeloid Leukemia - Full Text View - ClinicalTrials.gov In this, the dose is 1.3 mg/kg by a pediatric formulation, which is available only on the study, but please know that we do not have the PK data yet. There are some ongoing studies of asciminib + ATP-competitive TKIs (imatinib, dasatinib, nilotinib) for adult patients, but I am not aware of combination with ponatinib. In terms of ponatinib, there are also ongoing pediatric studies and the dose to be determined, but we have published a case series of ponatinib in children pubmed.ncbi.nlm.nih.gov/31975387/


FURTHER RESPONSE: Giuseppe Saglio

This is an extremely serious situation and the curative chances are very limited even after an alloBMT and almost absent without a transplantation or CAR-T cell therapy approach.

I think that it is important to know if we are in presence of two mutations in two different subclones or if we are in presence of compound mutations within the same clone. In the latter case the use of a single TKI is not effective and the only possibility is to combine ponatinib and asciminib. Due the dramatic situation I would not care so much about toxicity and, if the body weight is approximately 20 Kg, I would use ponatinib at least at 15 mg and Asciminib at 40-60 mg per day.

If there is an initial response and the % of the blast decreases I would also add blinatumomab as for R/R ALL cases (see scheme in Blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia: results of the RIALTO trial, Franco Locatelli, et al- Blood Cancer Journal volume 10, Article number: 77 (2020) and some intratechal chemo. However, even in case of a good response, I do not think that this situation could last long in absence of a subsequent alloBMT.
Moderators: Nicolaarlene