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Long-term Outcomes in the Chemo-free era for Acute Promyelocytic Leukemia (EHA2024) · EHA Unplugged

• 0:07
  Greetings and welcome to EHA Unplugged, the official podcast
• 0:11
  channel of the European Hematology Association.
• 0:14
  EHA as we know acute from myelocytic leukemia is a rare.
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  Subtype of. AML and accounts for about 10%.
• 0:25
  Of cases. 10 to 15% of cases and we can think that in Europe we.
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  Have APL. Diagnosed in about 450 patients
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  per year in. APL.
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  The T. 1517 translocation and the PML.
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  We are alpha. Rearrangement play a significant
• 0:49
  role and the leukemogenic. Activity of this.
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  Rearrangement is based on the retinoic acid receptor alpha,
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  which is rearranged with PML and this induces repression of.
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  RA, alpha target genes. And the differentiation block.
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  Which is typical of the disease. On the other hand, PML
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  rearranged to RA alpha. Loses its activity on.
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  Senescence and apoptosis and the.
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  Result is. Then an increased self renewal.
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  For this disease, we have the for the.
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  First time We've had some years ago now for the first time, a
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  targeted treatment which is based on 2.
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  Drugs which are able to target. The two moieties in the.
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  Translocations. ATRA targeting.
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  This retinoic acid receptor alpha and arsenic.
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  Trioxide, which targets. PML.
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  The result? Of the treatment of the
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  combination is the activation of differentiation.
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  Due to. Pharmacologic doses of.
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  Atra. And also the reactivation of
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  apoptosis. Due to the activity of.
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  All Trans retinoic. Acid.
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  Few additional mutations have been described in acute from
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  myelocytic leukemia and this. Is also due to this.
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  Strong leukemogenic. Activity of the.
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  Translocation. Some mutations in in RA, RA,
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  alpha, and PML genes have been rarely described, and these
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  mutations have been associated with resistance.
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  To ATRA. And.
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  Also to atoll. Also giving also a reason for
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  the importance. Of these.
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  Two moieties the outcome of APL. Has.
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  Been improving significantly. Over the years the pre Atra era
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  where the. Prognosis of APL.
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  Was. About 20%.
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  Survival at five years. With the addition of ATRA to
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  conventional chemotherapy starting in the 90s, we have
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  seen a significant improvement in survival and in this
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  situation. High risk.
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  APL have been defined. These were cases of APL with.
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  Increased white blood cell counts over 10,000, and these
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  patients had a significantly inferior prognosis when treated.
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  With. ATRA and chemotherapy.
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  Which was either rubicine. In most cases, later on with the
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  development of the combination of chemo 3 combination of.
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  Atra Plus. Arsenic trioxide outcome
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  significantly improved starting in 2006 and this was the time
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  when. The ATRA Auto.
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  Combination was used for patients relapsing after
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  conventional chemotherapy. Plus ATRA later.
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  On. We've had approval of ATRA Auto
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  as standard. Treatment for APL.
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  The pivotal trial. Published in the New England
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  Journal of Medicine in 2013 by an Italian German collaboration
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  and the trial. Was led by the late Francesco
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  Lococo. This trial was based on the use
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  of ATRA atom. For induction plus. 4 cycles of
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  consolidation versus. Aida regimen which consisted of
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  1 induction. Cycle +3.
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  Consolidation with chemotherapy and two years of maintenance
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  treatment. But six years follow up.
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  The chemo free treatment was associated with significantly
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  higher. Event Free survival.
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  Overall survival. Achieving 98% with ATRA.
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  Auto at six years versus. 89%. For.
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  The Aida chemotherapy. This was associated with a.
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  Significantly lower rate. Of short term side effects with
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  a. Reduced reduced probability of
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  thrombocytopenia and a neutropenia in patients treated.
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  With with the. Chemo free treatment.
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  But also. With an increased.
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  Rate of Leukocytosis due to the less toxic activity of ATRA, Ato
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  and. Also a higher rate of
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  differentiation syndrome and also.
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  With hepatic. Toxicity and QTC prolongation,
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  which we learnt to deal with later on.
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  This trial led to the approval of the of the.
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  Chemo free regiment for. Standard risk.
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  APL. In 2015.
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  By first FDA. And then EMA agencies in this.
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  Trial MRD. Was incorporated and we were
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  able. To show that.
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  Patients receiving. The ATRA Auto.
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  Combination similar to what happens with Aida chemotherapy
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  were all achieving MRD negativity.
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  After the 3rd consolidation, the kinetics of Atrato was a little.
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  Bit different from that of Aida in the sense that patients.
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  Treated with Atrato. Some patients were still.
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  Positive for the. PML RA alpha rearrangement after
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  induction, but they all converted to MRD negativity.
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  After the 3rd. Consolidation and this then?
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  Resulted as you. See here in a significantly
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  lower. Probability of relapse.
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  Only 1.7% in patients. Treated with attrato.
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  Versus 15% in patients. Treated with.
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  The Aida chemotherapy, the NCRIAML 17 trial and other
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  trials, and also. Real life studies.
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  Confirmed. Superiority of the.
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  Almost chemo free regimen. For APL as opposed to Aida like.
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  Chemotherapy only the UKA ML17 regimen was based on a slightly
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  different dosing of. Of auto twice.
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  Per week instead. Of five days per week as the as.
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  In the Italian German trial. So the.
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  Harmony Registry, which is a UEU funded project and nowadays
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  includes about 15,000 cases of acute myeloid leukemia,
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  represented a a very nice. Area where we could validate the
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  results of APL trials. In the real life and at longer
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  follow. Up so we were.
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  Able to analyze 1400 patients with APL at a median.
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  Follow up of five. And a half years and up to 14
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  years. These patients were derived.
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  From clinical trials and these. Were the APL O four O 6.
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  Trials and AML 17 and clinical practice from large European
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  cooperative. Groups.
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  Including Auvan. The AML static the group.
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  German and SSAL. Study group both these.
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  Are German study groups. The Swedish cooperative groups.
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  And more recently. Also the.
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  Austrolasian leukemia and lymphoma group 43% of.
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  These of the. Patients, including in the
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  Harmony. API registry were treated.
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  With chemo free. ATRA, Ato versus. 57% of the
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  patients receiving Aida like chemotherapy and 37% of the
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  patients derived from. Clinical trial versus 63% from
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  clinical practice. So we were also able to compare
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  outcomes of these. Two patients.
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  It is very clear A. Significantly superior outcome
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  for patients treated in with the chemo free regimen and the
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  survival of patients. Treated with Ultra at or
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  reached. About 90% at 10.
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  Years versus 70. 8% for Aida like chemotherapy.
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  This was of course associated with.
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  An improved event, free survival and used cumulative incidence.
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  Of relapse, which is about. 4%. For ATRA Auto.
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  Versus 14% for Aida like chemotherapy and among.
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  Variables associated. In the multi variable analysis
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  for survival for most outcome. Measures atra Ato.
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  Treatment remains an independent prognostic.
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  Factor for survival overall event.
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  Free and also for cumulative incidence.
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  Of relapse other. Important.
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  Factors are age. Over 50 and even more over 70
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  years. A high, high.
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  Risk score. And the clinical practice
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  scenario, we really think that evaluation of these outcomes is
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  also important for the. Aida like.
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  Chemotherapy regimen since we know.
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  That this. Regimen is still used in many
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  middle to low income countries. But however.
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  We took advantage. Of this court to look more
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  specifically at. Patients treated with.
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  Atra Ato despite a higher. Incidence of differentiation
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  syndrome which accounts in these patients.
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  For. About 10% and was associated.
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  With higher white. Blood cell counts and also.
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  Higher age. There were no differences in
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  event free. Survival.
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  Overall survival. And cumulative incidence of
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  relapse in the high versus standard science.
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  Risk score so. For the first time we have a
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  regimen where high. White blood cell.
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  Counts do not play a significant prognostic role, and we saw also
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  improved outcomes in. Clinical trials as expected
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  Where? Also reporting is more.
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  Accurate versus. Clinical practice and.
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  However, outcomes were better in the first during the first years
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  where. The Clinical.
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  Trials were performed as opposed to.
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  More recent. Years where we.
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  Have more patients treated in the clinical practice scenario
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  so since this. Is a disease.
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  Where we now achieve really long term survival and.
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  High probability of survival survivorship issues become.
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  Very important and the Gymema group.
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  With Fabio Ficace devoted a lot of effort to study quality of
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  life. In APL and what?
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  They were able to show was that. The physical component of.
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  Quality of life. Including displayer fatigue and
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  physical functioning was also significantly improved in
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  patients treated with. Atra Ato as opposed to.
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  Patients treated. With the Aida.
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  Chemotherapy and when looking at the patients receiving.
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  Atra Ato versus those. Those in the general population
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  not having APL, not receiving any chemotherapy.
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  The physical. Functioning of these patients
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  was. Similar to that.
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  Of the general population, if not better one particular.
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  Issue I would. Like to point.
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  Out is. Secondary leukemias, which are.
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  Part, of course, of the. Problems that we see in
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  patients. Who receive?
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  Chemotherapy for a primary tumor and.
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  After APL treated with Aida. Chemotherapy they were about 2%
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  of secondary leukemia on setting at about.
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  Two to three years from the. APL treatment and this was.
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  In the Aida epoch with Atra Ato. We don't really see secondary
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  leukemias and. Just few cases.
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  Have been reported. By the literature, so there are
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  still however. Some open issues 1I and I would
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  say the most important which. Still effects survival.
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  In these patients. Is early death.
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  You know. That early death is mostly due.
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  To bleeding complications and infectious complications.
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  Bleeding complications. Due to the disease itself.
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  We know that. There is hyper.
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  Fibrino lesis in patients with APL there is activation of a no.
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  Telia cells. Endothelial damage and release
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  of cytokines. Which induce then
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  differentiation syndrome and which induce?
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  Also. Bleeding so.
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  The rate of early death. Has been decreasing, but
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  nowadays we still unfortunately have about 19% of early death in
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  the Harmony project. We had a lot less which was
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  about 6. Percent, but we should think.
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  That that was that is a registry.
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  And there is under reporting in Harmony and the second open
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  issue and I would like to. Discuss Is high risk APL.
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  The ATRA Auto. Regimen is not in label.
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  For high risk APL, but we will see the results of the Apollo
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  trial, which is a phase. 3 randomized trial comparing Aida
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  like chemotherapy. To ATRA auto plus +2 doses of.
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  Milotarq. This is a pan European trial.
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  I I have here a picture of. Very nice statue from Lorenzo
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  Bernini at Museo. Borghese in Rome.
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  This in Rome, is the place where many.
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  APL studies were. Performed in the Jemima and by
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  Francesco Lococo. And in this statue, Daphne Nymph
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  escapes from Apollo by transforming herself into a LA
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  Room tree. In our case, Apollo wins.
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  The Apollo trial showed a. Significant advantage for the
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  chemo free regiment also in high.
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  Risk APL. The last issue is oral.
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  Arsenic. We know that oral arsenic has
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  been used in many Chinese studies and also in the
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  clinical. Practice also by.
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  Asian. By the APL.
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  Asian Consortium project and this is a.
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  Total Oral. Combination and you see.
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  Here a very. Prolonged overall.
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  And eventually, survival. For patients treated with.
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  The total oral. Combination.
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  This combination is. Particularly attractive for.
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  Consolidation treatment. Since of course.
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  We need to see during consolidation, we need to see
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  patients less in our outpatient clinics and this.
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  Will be we will save a lot of resources if the results would
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  be confirmed. And I would like to thank all
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  my. Collaborators so I.
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  Think we have time for a few questions?
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  So just one question, what do you think about the possibility
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  of arsenium to to penetrate blood barrier for meningeal
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  localisation of the disease? Yes, actually it has been shown
• 17:47
  that arsenic. Trioxide penetrates the
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  barriers. And so we don't see many extra
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  medullary relapses in patients. Treated first.
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  Line with arsenic. Trioxide.
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  I think that this is an issue. That we will have to deal.
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  With more. With high risk APL so.
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  We are going to to analyse our data on.
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  The Apollo trial. Also looking into.
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  That. I can tell.
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  You that so far there is. Not, you know.
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  Also the rate of early relapses up to two years of follow up is
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  decreased in ATRA auto treated high risk.
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  APL patients and this includes also extramedullary relapse.
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  But you're right. Frequently patients who.
• 18:40
  Relapse do show. CNS localisation but.
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  This. I mean.
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  There will be. A minority of patients with that
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  complication, but with. ATRA auto first.
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  Line. Should be less.