Gianfranco Catalano1,2,3, Pasquale Niscola3, Cristina Banella1,2, Daniela Diverio4, Malgorzata Monika Trawinska, Stefano Fratoni5, Rita Iazzoni6, Paolo De Fabritiis1,3, Elisabetta Abruzzese3* and Nelida Ines Noguera1,2*.
1 Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy.
2 Neuro Oncohematology Unit, Santa Lucia Foundation, IRCCS. Rome, Italy.
3 Hematology Unit, Sant’ Eugenio Hospital, Tor Vergata University of Rome, Rome, Italy.
4 Hematology, Department of Precision and Translational Medicine, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy.
5 Department of Pathology (UOSD Anatomia Patologica) A.S.L. Roma2, Sant’ Eugenio Hospital, Rome, Italy.
6 Department of Clinical Pathology (U.O.C. Laboratorio) A.S.L. Roma2, Sant’ Eugenio Hospital, Rome, Italy.
Elisabetta Abruzzese. Hematology Unit, Saint’ Eugenio Hospital, Tor Vergata University of Rome, 00133 Rome, Italy. E-mail: email@example.com
Received: August 26, 2020
Accepted: October 22, 2020
Mediterr J Hematol Infect Dis 2020, 12(1): e2020083 DOI 10.4084/MJHID.2020.083
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
cluster region - Abelson (BCR-ABL1) chimeric protein and mutated
Nucleophosmin (NPM1) are often present in hematological cancers, but
they rarely coexist in the same disease. Both anomalies are considered
founder mutations that inhibit differentiation and apoptosis, but
BCR-ABL1 could act as a secondary mutation conferring a proliferative
advantage to a pre-neoplastic clone. The 2016 World Health Organization
(WHO) classification lists the provisional acute myeloid leukemia (AML)
with BCR-ABL1, which must be diagnosed differentially from the rare
blast phase (BP) onset of chronic myeloid leukemia (CML), mainly
because of the different therapeutic approach in the use of tyrosine
kinase inhibitors (TKI). Here we review the BCR/ABL1 plus NPMc+
published cases since 1975 and describe a case from our institution in
order to discuss the clinical and molecular features of this rare
combination, and report the latest acquisition about an occurrence that
could pertain either to the rare AML BCR-ABL1 positive or the even
rarer CML-BP with mutated NPM1 at the onset. Differential diagnosis is
based on careful analysis of genotypic and phenotypic features and
anamnestic, clinical evolution, and background data. Therapeutic
decisions must consider the broader clinical aspects, the comparatively
mild effects of TKI therapy versus the great benefit that might bring
to most of the patients, as may be incidentally demonstrated by our
t(9;22)(q34.1;q11.2) BCR-ABL. Among human cancers, AMLs are relatively genetically simple and stable diseases featuring the fewest mutations variety and average. AML genomes contain a median of 13 coding mutations (single nucleotide variants and insertion/deletions) and an average of less than one gene-fusion event.[7,8] Most of the fusions derive from translocation events, and Philadelphia chromosome t(9;22)(q34.1;q11.2), generating the BCR-ABL1 chimeric protein, was the first genetic aberration associated with human cancer: Chronic myeloid leukemia (CML). BCR-ABL activates proliferation signaling pathways (RAS and STAT5, STAT1 and STAT6 signaling, PI3-K and AKT/PKB pathways), analogously to PML/RARa in APL inhibits PTEN,[9,10] interferes with the focal adhesion complex (PAXILLIN, FAK), induces abnormal integrin signaling (FAK/CRK-L/SDF-1) and has anti-apoptotic activity (PI63K/Akt/STAT5). In addition, BCR-ABL has been shown to generate a “mutator” phenotype downregulating homeostatic controls and DNA repair pathways and promoting the expression of DNA-polymerase-beta, which is prone to copy errors during DNA replication. Since no CML-BP with lymphoid phenotype carrying the NPM1c+ mutation was ever reported, we will not address the subject of Ph1+ALL. Contrarily to what could be expected only a few years ago, myeloid neoplasms carrying the BCR-ABL transcripts are a composite subset of hematological disorders. If the principal disease, CML, in which BCR-ABL1 is involved, has well-characterized features and standardized diagnosis and therapy, the picture is composite for the other neoplastic diseases. 2016 WHO classification of myeloid neoplasms and acute leukemia distinguish, other than CML, two more entities: one mixed phenotype acute leukemia (MPAL) with BCR-ABL1, and the provisional AML with BCR-ABL1. Since no CML-BP with lymphoid phenotype carrying the NPM1c+ mutation was ever reported, we will not address the subject of Ph1+ALL.
Nucleophosmin. Nucleophosmin (NPM1) is present in high quantities in the granular region of nucleoli but shuttles between nucleus and cytoplasm, acting as a chaperone. Chaperones are molecules that associate with target proteins, organize their structure, convoy them to the appropriate place, and molecular aggregate but are not part and have no function in that aggregate.[12,13] NPM1 has been identified as the most frequently mutated gene in AML patients, accounting for about 30% of cases,[14–16] the vast majority of which with normal karyotype. At onset, NPM1 mutation associates with a less severe prognosis, but clonal evolution can lead to additional genetic abnormalities and worst prognosis.[1,16,17] NPM1 gene mutations in AML lead to a new C-terminus sequence in the mutant protein, that, as compared to the wild-type protein, lacks the nucleolar binding site and acquires a nuclear export signal: mutated NPM1 is confined to cytoplasm, its absence from the nucleus seems to be the basis for the oncogenic phenotype since the protein plays a role in chromatin remodeling, centrosome duplication, DNA replication, recombination, transcription, and repair as well as in the control of cell cycle progression and survival in response to a variety of stress stimuli.[12,18–21]
The Paradigm of Leukemogenesis. Mutations within a cell can influence the rate of acquisition of other lesions. After the initiating mutation, there might be a gradual accumulation of additional genetic alterations or accelerated progression due to genomic instability or catastrophic genetic events, including chromothripsis.[22–27] The number of identifiable driver mutations differs between AML cases. Although most cases harbor three or more identifiable drivers at the time of clinical presentation, human sequencing data describe many AML with only one or two identifiable driver mutations.[24,28] According to the model of Gilliland and Griffin, the paradigm of leukemogenesis features a class II mutation as leukemia-initiating event, causing inhibition of differentiation and apoptosis, cooperating with a class I mutations conferring a proliferative advantage to the clone.[29,30] In 2013 the Cancer Genome Atlas Research Network classified three sets of genes with the strongest patterns of mutual exclusivity. For the purpose, they used whole genome or whole exome sequencing and statistical analysis of 200 de novo AML cases selected from a set of more than 400 samples to reflect a real-world distribution of subtypes. The first set comprised the transcription-factor fusion genes and mutations involving NPM1, RUNX1, TP53, and CEBPA, the second set the mutations in genes encoding FLT3 or other tyrosine kinases (TK), serine-threonine kinases, protein tyrosine phosphatases, RAS family proteins, and the third set included mutations in ASXL1 and genes encoding components of the cohesin complex, other myeloid transcription factors, and other epigenetic modifiers. The association of BCR-ABL1 and mutated NPM1 in the same clone is unusual but not contradictory to either of the models if NPM1 is the founder, class II mutation, and BCR-ABL1 acts a class I mutation, conferring a proliferative advantage to the affected cells. BCR-ABL1, even though capable of transforming hemopoietic stem cells single-handed and causing per se CML and diverse acute leukemias (Ph1+ ALL, MPAL and AML), could be working as a class I mutation since the molecular aberration was found in tumor subclones and even in oligoclones in otherwise normal bone marrow.[32,33] However, would that be possible to reverse the rank of the mutations, as in a CML blastic phase (CML-BP) clone carrying mutated NPM1 evolving from an NPM1-negative chronic phase disease? Moreover, how to discriminate between de novo Philadelphia positive AML and a CML diagnosed at BP onset? Even though identical regarding two substantial features of the genetic profile, the two conditions must have different biology. The presence of BCR-ABL1 protein ab initio, thus in tumor-initiating cells and all the disease clones, must confer the phenotype, natural history, and clinic of CML. Conversely, the emergence of a BCR-ABL positive clone as a type I mutation in an NPM1 mutation expressing clone is not more than a concomitant feature in the characteristic of acute leukemia, in a way not entirely different from a FLT3 activating mutation (Figure 1).
NPM1 Mutated and BCR-ABL1 Positive Myeloid Neoplasm
1.AML with BCR-ABL1 and NPM1 mutations.
From the clinical point of view, sometimes the presence of the BCR-ABL1 hybrid transcript could not clarify the adjudication since a precise distinction between AML and CML-BP at onset is still to be defined, which poses problems of diagnosis and therapy, most of all about the timing and efficacy of TKI therapy. Notwithstanding the rarity of cases, it seems clear that AML with BCR-ABL1, in general, does not always respond well to TKI therapy ; conversely, a TKI naïve CML must benefit from TKI therapy.
Experience in Our Institution. Here we want to narrate the case of a patient, 43 years of age, male, diagnosed in April 2013 at a different country institution supposedly with a CML onset in BP and treated with 3 days Idarubicin plus seven days of high dose Aracytin (IA 3+7) resulting in complete hematological remission on day 26. The patient had experienced a series of severe complications during the induction therapy. The routine molecular assessment had documented positivity for BCR-ABL1 (p210-B3A2) translocation and NPM1 mutation A.[42,43] The patient, with residual hepatic toxicity, was prescribed Dasatinib 100mgr as maintenance therapy. The diagnosis was well documented as for the extension of the search for the mutations but essential since we were not detailed about the FAB and immunophenotype of the blasts, quantities of the mutated transcripts, or about any other clinical aspect that would explain the choice of CML-BP over AML with BCR-ABL1+. In our opinion is of interest that the case was labeled as CML-BP, yet the clinical perspective and indication were that of a de novo AML with BCR-ABL1: intensive induction chemotherapy with additional TKI maintenance therapy, then consolidation and allo-SCT.
On day 45, our bone marrow evaluation showed hematologic morphologic remission, molecular remission of the BCR-ABL1 transcript (p210 transcript was 0.069% with MR3 sensitivity, p190 was 0,0% negative MR3 sensitivity) and molecular remission of the NPM1 mutated transcript (0.025 of NPM1 mutation A copies every 104 copies of ABL, cut off value 0.03). Of note that only a small percentage, less than 10%, of CML-BP patients, achieves molecular remission after frontline chemotherapy plus TKI therapy. In contrast, almost one in three of AML NPM1 mutated patients achieve molecular remission 30 days after frontline therapy. The search for a compatible donor among siblings was unsuccessful, we consulted with the patient. We agreed to postpone intensive chemotherapy mainly for the high risk of a recurrence of the intestinal bleeding, at the same time the patient did not agree to start a search for an unrelated compatible donor. One year since onset p210 transcript was undetectable with MR5 sensitivity, we stop essaying p190, and the NPM1 mutated transcript remained in molecular remission (0.03 of NPM1 mutation A copies every 104 copies of ABL, cut off value 0.03). After more than 6 years, the patient is still in continuous profound molecular remission of the BCR-ABL1 (undetectable transcript with MR5 sensitivity) and remission of the NPM1 transcripts. Still assuming Dasatinib, the dose was interrupted for 30 days and then reduced by half to 50 mg per day due to a chemical pleuritis about 12 months ago. The interruption and lowered dose did not cause any variation in the molecular remission of both transcripts. Since all disease-free survival (DFS) curves tend to plateau after 2-3 years of follow-up and relapse after 5 years of DFS are rare events, we may say the patient was fortunate not to undergo intensive chemotherapy and allo-SCT.
Nevertheless, is this patient eligible for ending TKI therapy? It all depends on the diagnosis. A CML-BP in remission is not eligible in any case for stopping TKI therapy. Conversely, an AML in continuous molecular remission after 6 years could be considered for ending the treatment.
The presence of lymphoid markers, not sufficient for a classification as MPAL according to WHO, is in line with a finding by Atfy et al., who found in all nine cases of de novo Ph1+ AML: CD33 and CD13 markers, and CD64 in 8 of them. MPO was positive in 9/9 patients by flow cytometry. The B-lymphoid marker CD79a was positive in one, T-lymphoid marker CD7 in 4, CD24 in one case, and CD19 was found in two AML cases that could be considered as FAB M2. Seven of the nine AML patients had an aberrant expression of lymphoid markers. Stem cell markers CD34 were positive in 6/9, and TDT was positive in 1/9 cases. According to the FAB, one case was diagnosed as M0, 3 cases as M1, 4 cases as M2, and one case as M4.
In a recent study among 46 cases of myeloid BP, 76% expressed CD34, and 74% expressed CD117. Myeloperoxidase expression was noted in a variable proportion of precursor cells in 85% of cases. TDT was expressed in 37% cases, 14 cases expressed markers outside of the standard myeloid phenotype, and two expressed markers of more than one lineage (B or/and T).
In a retrospective study of 477 BP cases in 20 years encompassing the introduction of TKI therapy, Jain P et al. found that, for 77 patients diagnosed as BP at the onset, first-line treatment included TKI alone (24 patients; 34%), TKI plus chemotherapy (41 patients; 58%), non-TKI-based therapies (2 patients; 3%). Clonal evolution under therapy pressure must play a role since patients with de novo BP had a longer overall survival time (OS) compared with patients who transformed from CML-Chronic Phase/CML-Acute Phase (P<.0001). The most effective treatment option was the combination of a TKI with chemotherapy. Patients who achieved morphologic hematologic remission (MHR) or complete cytogenetic remission (CCyR) or major molecular response (MMR) after initial BP treatment had a significantly longer failure-free survival (FFS) (P<.0001) and the achievement of MHR and/or CCyR emerged as the most significant independent predictors of survival. In a 2019 review, Soverini et al. state that 2 to 5% of CML patients present in accelerated phase (AP) and 2 to 7% in BP and that, as a whole, AP/BP patients display a high degree of genetic instability, with an accumulation of additional genetic and cytogenetic abnormalities that reduce sensitivity to TKI. However, the paper does not address the genetics of de novo AP/BP patients.
In a study published in 2015, Klco et al. confirm that among 71 patients with de novo AML, 18 patients carrying NPM1 mutated alleles were cleared below the threshold of 2,5% (5% of cells) at day 30 from induction therapy start, and those patients have the best chances to have a long first remission. Seemingly type I mutations as FLT3, KRAS, or NRAS were usually cleared on day 30, suggesting that subclones containing these mutations may be highly sensitive to induction chemotherapy, but of course, those patients tend to relapse early and have a poor prognosis.
Thus would not be unusual that in our case, if considered as an AML, the molecular profile was nearly negative for both mutations on day 45. Conversely, a CML-BP in hematological remission after just one intensive chemotherapy cycle and after no more than 18 days of TKI therapy should register at least a substantial regrowth of clonal BCR-ABL1 positive hematopoiesis. As exposed before, there are several suggestions but not certainty about discriminating de novo Ph1+AML and CML-BP at the onset. In the absence of a previous CML history, differential diagnosis is based on the global analysis of histologic, immunophenotype, and genetic features, which in most cases singularly are not decisive in differentiating the two conditions, but taken all together may lead to a possible assignation. We summarize the differential characteristics in Table 2. It is interesting as some statistical modeling reports implicate the role of functional NPM1 in conveying tumorigenic signals from the BCR-ABL1 oncoprotein to ribosome biogenesis, affecting cellular growth.[52,53] Thus, in theory, NPM1 mutation could hamper, in part, BCR-ABL1 oncogenic phenotype, which explains the rarity of the finding and renders NPM1 a highly improbable candidate for BP transition.
|Table 2. Differential characteristics between CML-BP and AML.
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