1
Assistant professor of Hematology/Oncology, Lorestan University of Medical Sciences,
Department of pediatrics, Lorestan, Iran (Islamic Republic of)
2
Associate Professor of Pediatric Hematology/Oncology, Shiraz University of Medical Sciences, Shiraz, Iran (Islamic Republic of)
Corresponding author details:
Omidreza Zekavat
Associate professor of Pediatric Hematology/ Oncology
Shiraz University of Medical Sciences
Shiraz,Iran (Islamic Republic of)
Copyright:
© 2019 Abdolkarimi B.
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Mixed Phenotype Acute Leukemia (MPAL) is a unequal subgroup in the World Health Organization classification that includes acute leukemia’s with separate mixed populations of myeloid and lymphoid (“bilinear”) or coexpression blasts large amounts of lymphoid and myeloid markers in a single population of blasts (“Biphenotypic”). The flow cytometrydatas suggestive of MPAL are often met with confusion by pathologists and oncologists, due to unfamiliarity with the disease and uncertainty about how MPAL fits into established paradigms for the treatment of acute leukemia[1].
The consensus criteria for the diagnosis of AMLL were established in 1995. The European Group for the Immunological Characterization of Leukemia (EGIL) has famous a scoring system for the immunological classification of acute leukemia. Base on the characteristics of the leukemic cells with respect to the expression of the antigen and the cellular source, the AMLL phenotype can be divided into bifenotypic, bilinear and biclonal types (including the type of conversion). In addition, other researchers have advised the morphological and cellular chemistry characteristics to support the calls AML Ly +or ALL My + [1]. But, in fact, the diagnosis of AMLL is very difficult and its clinical significance and prognosis are not entirely clear [2].(Figure 1, Figure 2)
There isn’t a classical protocol for MPLA, so this article suggests best chemotherapy
protocol for MPAL, as an unusual leukemia’sbased on actual documents.
Figure 1: World Health Organization 2008/2016 Criteria for Mixed-phenotype Blasts a
Abbreviations: MPO, Myeloperoxidase, NSE, Nonspecific Esterase.
a
Data derived from Borowitz et al.[6] and Arber et al. [7]
b
Strong= at least as intense as in normal B or T cells.
Figure 2: European Group for Immunological Characterization of
Acute Leukemias (EGIL) Algorithm for Biphenotypic Blasts a,b
Abbreviations: CY, Cytoplasmic; IGM, Immunoglobin M; MPO,
Myeloperoxidase; SM, Surface Membrane; TCR, T-Cell Receptor;
TDT, Terminal Deoxynucleotidyl Transferase.
a
Biphenotypic leukaemia is diagnosed when scores are greater
than 2 in 2 lineage columns.
b
Data derived from Bene et. al. [5]
Case reports from different centers or countries tend to test all cases of acute leukemia and describe MPAL in 2 to 3% of the population.
We treat with an ALL regimen and consolidate with an alloSCT if a donor isavailable.
The Mostly complete remission rate is higher with ALL treatment or a combined ALL / AML chemotherapy regimen than with AML-type therapy even in many patients who had morphological AML (85% CR rate compared to 41% for AML type therapy). This phenomenon showed that the morphology of the explosion is not useful for the selection of the trend of the chemotherapy regimen (bases ALL or base AML). The etiology of this discorelated response is unknown [3,4].
While many of the suggestions have been to use ALL-type therapy, the situation is not always correct. Therefore, the use of the combined regimens of AML + ALL has some advises (the VAPA approach includes: vincristine 1.5 mg / m2, doxorubicin 30 mg / m2 for 3 days, prednisolone and Ara-C 100 mg / ( m2 day) But some reports were found These regimens are quite toxic compared to the popular ALL. protocols [5].
Patients with MPAL when they achieve complete remission should have an allogenic SCT, depending on a high probability of early relapse. There was a 5-year OS rate of 70% compared to 19% for those who received chemotherapy alone.
Minimal Residual Disease (MRD) in MPAL cases can be challenging, although flow cytometry is administered to define MRD [6].
Patients who clearly have MRD at the beginning of their course may be managed by consolidation chemotherapy instead of allogenic SCT in a manner similar to ALL Ph+ that becomes molecularly negative after therapy. Chemotherapy alone would be insufficient to eradicate the disease[3-6].
MPAL is incurable without a stem cell transplant; the same probable Ph + AML and AML associated with MDS and / or adverse to the chromosome.
In MPAL, the initiation of treatment with ALL or a combined
regimen is more logical than an AML regimen, especially the
administer of Ara-C in the latter, less useful against a primitive stem
cell that divides slowly [7].
The only special patients within the MPAL WHO classification are caseswith (9;22) or 11q23 cytogenetic abnormalities. Now, considerations chemotherapy for those with cytogenetic abnormality similar11q23 isnot different from those for MPAL with any nonPhiladelphia cytogenetic [8].
However, the 11q23- rearranged cases should be advised to some novel agents if chemotherapy and allogenic HSCT fail or if the patient is not a candidate for aggressive chemotherapy. Such therapy could include a histone-modifying–enzyme inhibitor or an inhibitor based on the primary molecular abnormality or target therapy downstream activation of Hox genes via glycogen synthase kinase 3 or b-catenin inhibitors [3-10].
In Ph + MPAL we should use Tyrosine Kinase Inhibitor (TKI) such as Imatinib or Dsatinib combinated with chemotherapy followed by alloSCT.
This subtype is approximately 25% of all MPALs with poor prognosis. ALL Ph+ was historically considered an entity with poor prognosis, but prospective studies in which Imatinib or Dasatinib was combined with chemotherapy increased disease-free survival (DFS) from 40% to 60%. Although patients with Ph + ALL achieve remission with TKI plus chemotherapy and then they must be consolidated with alloSCT if there is a full compatible donor available [3-9].
Autologous bone marrow transplant for patients with ALL Ph+ in remission and / or TKI in progress since maintenance may be associated in the long termremission, if the patient has not full matched donor.
For older adults, excellent short-term results have been obtained with Dasatinib plus steroids and intrathecal chemotherapy[9].
Therefore, we treat all patients with MPAL with t (9; 22) by chemotherapy with age-specific ALL (CALGB hyperCVAD, MRCECOG) for middle-aged patientsand the FOA regimen for elderly patients in combination with a TKI followed by allogenic HSCT[10].
In some pediatric and adult reports, it was reported that biphenotypic expression was associated with a high frequency of involvement of the central nervous system (CNS) in the first presentation. The result of the use of pediatric-type chemotherapy plus TKI for cases under 40 years of age with MPAL + Ph is not clear[11].
The results of patients with MPAL PhAL with patients with Ph+ ALL showed a significant difference in completeremission rates between the 2 groups (100% vs. 85%), as well as a 5-year OS (55% vs. 53%) and disease free survival (DFS) (46% vs 42%)[12] (Figure 3) (Table 1, Table 2).
If the patient is in remission after consolidation phase and the patient has full Matched donor line A is recommend,but if the patient is in remission after consolidation phase and the patient hasn’tfull matched donor line B is recommend (Table 3 A, B).
If the patient is in remission after consolidation phase and the
patient hasn’tfull Matched donor line C is recommend as targeted
therapy:
Figure 3: The approach to therapy in patients with mixedphenotype acute leukaemia (MPAL). Targeted therapy based
on a patient’s specific genetic profile should be considered in
refractaorylrelapse patients (eg. MLL rearrangements, FLT3-ITD,
IDH1, IDH2).
a
Consider Pediatric inspired protocol if <40 years old (in which
case transplant in first remission not generally indicated)
b
For example High-Dose Cytarabine and Mitoxantrone (HAM).
Table 1: Induction (1 month)
Table 2: Consolidation (EACE)
Table 3: Line A (after BM recovery, if ANC > 500 and plt> 100,000)
Table 3: Line B if the patient is in remission after consolidation phase and the patient hasn’tfull Matched donor line C is recommend as
targeted therapy.
Mixed-phenotype acute leukemia is a diagnostic and therapeutic
challenge owing to its heterogeneity, overlapping features with other
types of ALL and AML, and lineage plasticity.Because MPLA patients
are rare, controversial topicsabouttreatment of these patients are
many .Weneed to many clinical trials to introduce safe and effective
chemotherapy regimen which hasn’t been mortality before bone
marrow transplantation.
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