Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Chronic Myeloid Leukemia and Polycythemia Vera Progression

  • Hans H. KreipeEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_3858-1

Synonyms

Definition

Myeloproliferative neoplasms, including chronic myeloid leukemia (CML) and polycythemia vera (PV), may progress from a steady-state phase (chronic phase) with sufficient production of mature blood cells to an accelerated phase with deterioration of hematologic blood parameters and/or organomegaly. Chronic and accelerated phase may be followed by a blast phase with more than 20% immature blasts in the blood or bone marrow. Transition from chronic to accelerated and blast phase, respectively, is defined by varying parameters, which according to WHO (Vardiman et al. 2017) are summarized in Table 1.
Table 1

Accelerated and blast phase in CML and PV

 

Accelerate phasea

Blast phase

CML

Persistent or increasing white blood cell count (>10 3 × 109/L)

Persistent or increasing splenomegaly

Persistent thrombocytosis (>1000 × 109/L)

Persistent thrombocytopenia (<100 × 109/L) unrelated to therapy

20% or more blood basophils

10%–19% blasts in the blood or bone marrow

Additional clonal chromosomal abnormalities (second Ph, trisomy 8, isochromosome 17q, trisomy 19, complex karyotype, or abnormalities of 3q26.2)

Any new clonal chromosomal abnormality in Ph1 cells that occurs during therapy

Tyrosine kinase inhibitor resistanceb

≥20% blasts in the bone marrow and/or peripheral blood

Extramedullary blast proliferation

PV

Spent phase, post-polycythemic myelofibrosis

Leucoerythroblastic blood smear

Bone marrow fibrosis

Decreasing blood cell counts and increasing splenomegaly

Leukocytosis like in atypical CML or chronic myelomonocytic leukemia

10%–19% blasts in the blood or bone marrow

≥20% blasts in the bone marrow and/or peripheral blood

Extramedullary blast proliferation

aIn PV, acceleration is not an established term. In general use are designations as spent phase and post-polycythemic myelofibrosis

bSee text

The accelerated phase in CML is characterized by an increase of blast cell counts either in the peripheral blood or the bone marrow or in both compartments. In parallel or alternatively, other parameters may indicate transition from the chronic to the accelerated phase, such as increase of basophils in the peripheral blood, persistent thrombocytopenia or thrombocytosis, increasing white blood cell counts, or increasing spleen size despite therapy (Table 1). The definition of acceleration is also encompassing either karyotypic evolution and/or emergence of therapy resistance (Baccarani et al. 2009). The blast phase in CML is defined by blast cell count of ≥20% either in the peripheral blood and/or the bone marrow. Likewise, the occurrence of either extramedullary blast infiltrates or intramedullary large aggregates of blast cells defines the transition from chronic to blast phase (Table 1).

In clinical practice, progression in PV is usually designated with terms like spent phase or post-polycythemic myelofibrosis. Unlike CML acceleration, it is less clearly defined. There are different parameters which indicate progressive disease. Development of myelofibrosis; increasing splenomegaly; lowering of blood cell counts, in particular of erythrocytes and thrombocytes; and rise in granulocyte counts with left shift in the peripheral blood are considered to be indicators of progression or acceleration (Table 1). In approximately one third of patients with these signs of progression blast crisis evolves. Rarely, blast crisis develops without preceding fibrotic progression. For post-PV myelofibrosis, a catalogue of criteria besides manifest fibrosis of the bone marrow (grades 2, 3) has been proposed. From these four criteria, at least two should be present to settle the diagnosis. These criteria include anemia, leucoerythroblastic blood picture, increasing splenomegaly (plus 5 cm above baseline), constitutional symptoms (two of the three following: >10% weight loss in 6 months, night sweats, fever without obvious cause) (Barosi et al. 2008).

Clinical Features

  • Incidence

    The incidence of progression in CML has changed dramatically since the introduction of tyrosine kinase inhibitors (TKI) into therapy. The chronic phase in CML has historically lasted for 3–4 years with a progression rate to blast crisis in the first 2 years of 5–10% and thereafter of 20–25% per year. Untreated patients will invariably develop progression mostly within 3–4 years after diagnosis (Kantarjian et al. 1988). In the era of TKI treatment, the 5-year progression-free survival is 80–95%. Disease progression to advanced phase (accelerated or blast phase) has been reduced to 1–1.5% per year from more than 20% per year in the pre-TKI era (Mukherjee and Kalaycio 2016). In PV about 15% of patients develop progression after 10–15 years after initial diagnosis, after 20 years the rate amounts to 25% (Silverstein 1976).

  • Age

    The median age of progression is about 3 years later than the median age of diagnosis in CML (65 years). CML can occur in any age, including childhood. In PV the median age of progression is about 15 years later than the median age of initial diagnosis (60 years).

  • Sex

    In CML and PV including progression, there is a slight male predominance.

  • Site

    Progression to blast phase in CML and PV may occur in the bone marrow, spleen, or other extramedullary sites.

  • Treatment

    TKI have moderately improved survival in the blast phase of CML. First-generation TKI (imatinib) are differentiated from second- (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) TKI, respectively. Alternative treatment modalities are intensive chemotherapy and allo-stem cell transplantation. TKI-treated patients in the chronic phase who have achieved major molecular response enjoy durable responses with virtually no current progression to accelerated phase or blast crisis (Steegmann et al. 2016). Patients who have achieved stable complete molecular remission may experience in approximately 40% of cases complete continued remission in the absence of maintenance treatment (Steegmann et al. 2016). In the accelerated phase, dosage increase of TKI may be successful (Deininger 2015). Progressed PV is treated with JAK2 inhibitors and in selected cases with allogenic stem cell transplantation (Vannucchi and Harrison 2017). In the blast phase of PV, diverse regimes with limited success are used, including hypomethylating agents, low-dose chemotherapy, induction chemotherapy, and allogeneic stem cell transplantation.

  • Outcome

    The prognosis of CML patients in the blast phase is dismal with median survival ranging from 7 to 11 months (Hehlmann et al. 2016). With acceleration and progression, the prognosis in PV worsens and resembles progressed myelofibrosis or MDS. About 3–7% of patients progress to blast phase with an unfavorable outcome like in CML (Vannucchi and Harrison 2017).

Macroscopy

Accelerated phase in CML and PV may be associated with splenomegaly. Usually the spleen is diffusely enlarged without tumor formation and the consistency is increased. In the blast phase of CML and PV, there might be tumor formations affecting lymph nodes or extranodal sites and hepatomegaly.

Microscopy

Acceleration in CML may become morphologically manifest in the peripheral blood as well as the bone marrow. In the peripheral blood, increased number of blast cells may occur besides immature precursor cells (Fig. 1). If there are ≥20% blasts in the peripheral blood and/or the bone marrow, it is no longer called acceleration but blast crisis. In some cases basophilia which is a regular phenomenon in CML may increase. If the percentage is >20%, increased basophilia is considered as evidence for acceleration (Fig. 2). In TKI-treated patients, blast increase during acceleration may be combined with low cellularity and suppression of granulopoiesis (Fig. 3). Frequently fibrosis of grade 1 or grade 2 can be found. Resistance against TKIs may develop during treatment and also indicates acceleration. Infrequently, signs of acceleration such as splenomegaly are noted clinically, but the level of BCR-ABL transcripts remains low. In these cases, bone marrow biopsy may reveal a shift of phenotype with atypical megakaryocytes resembling those from BCR-ABL-negative myeloproliferative neoplasms and myelofibrosis (Fig. 4). Combination of JAK2V617F mutation and BCR-ABL junction are found in these cases. Treatment with TKI suppresses the BCR-ABL clone, whereas the JAK2-mutated clone remains unaffected.
Fig. 1

Blast cells occurring in the peripheral blood as indicators of progression in CML. Two immature blasts besides granulocytic precursors and mature granulocytes can be seen (Pappenheim, ×400)

Fig. 2

An increase of basophil counts in the peripheral blood or bone marrow indicates acceleration. Four basophils besides atypical granulocytes and one monocyte are shown (Pappenheim ×400)

Fig. 3

Acceleration in CML is demonstrated by an increase of blasts in the left shifted granulopoiesis. Cellularity, in particular myelopoiesis, is reduced due to imatinib treatment (Giemsa)

Fig. 4

In this case of CML treated with imatinib, clinically diagnosed therapy resistance was due to a simultaneous JAK2 mutation. The corresponding clone became visible after the BCR-ABL-positive clone had been successfully suppressed by TKI and led to a shift of phenotype. Huge clustering megakaryocytes and myelofibrosis indicated JAK2-mutated myeloproliferative neoplasm (Giemsa ×250)

Blast crisis is diagnosed when the blast content in the peripheral blood or the bone marrow exceeds 19% or when extramedullary myeloid sarcoma develops. Blast crisis in most instances resembles acute myeloid leukemia, and in about 30% of cases, it shows the phenotype of acute lymphoblastic leukemia (Reid et al. 2009). Myeloid blast crisis represents the complete spectrum of acute myeloid leukemia. Blast populations may be devoid of any maturation or can show different degrees of maturation. In addition, promyelocytic, myelomonocytic, erythroblastic, or megakaryoblastic phenotypes may be encountered during blast crisis. Sometimes blast cells represent immature basophils, and blast crisis may emerge in conjunction with basophilia. In rare cases blast crisis shows the phenotype of acute megakaryoblastic leukemia (Fig. 5).
Fig. 5

Blast crisis of CML with a megakaryoblastic phenotype (Giemsa)

The major clinical complications in PV, unlike CML, are not provided by blastic progression but by thrombosis and hemorrhage. Progression develops in about 15–25% of patients after 10 to 20 years. In progressive disease with developing or manifest myelofibrosis, the peripheral blood shows an increase and left shift of granulocytic cell. Furthermore, erythrocyte precursors, namely, normoblasts, may occur in the peripheral blood (leucoerythroblastosis). In the bone marrow, a reduction of erythroid islands and an exaggerated granulocytic proliferation with a more or less pronounced left shift (Fig. 6) can be seen. Granulocytic proliferation is accompanied by granulocytosis and occurrence of immature myeloid precursor cells in the peripheral blood. Frequently, also an increase in fiber content can be noted (Fig. 7). Sometimes the monocytic lineage dominates, and together with a peripheral absolute and relative monocytosis, this presentation of accelerated phase resembles chronic myelomonocytic leukemia (Fig. 8). In rare cases worsening of clinical findings such as decreasing blood cell counts and increasing splenomegaly is accompanied by enlarged erythroid islands which almost completely consist of proerythroblasts and do not show maturation to normoblasts anymore (Fig. 9). In these cases fusion of the JAK2 gene with other genes has been demonstrated (Fig. 9).
Fig. 6

Progression in PV is frequently accompanied by an exaggerated proliferation of the megakaryocytic lineage with predominance of maturing myeloid cells, whereas erythropoiesis appears to be relatively reduced. Enlarged megakaryocytes are still visible (Giemsa)

Fig. 7

Progression in PV may be accompanied by an increase of reticulin fibers as demonstrable in this case of long-standing PV. Besides fibrosis (grade 2), small-sized megakaryocytes like in MDS can be seen (Gomori)

Fig. 8

In this case of PV, monocytosis developed and bone marrow biopsy revealed an increase of mature and immature monocytes resembling chronic myelomonocytic leukemia (Giemsa)

Fig. 9

Rarely, progression in PV may show enlarged erythroblastic islands in peritrabecular localization (upper right corner). A translocation t(9;11) found in this case most likely affected the JAK2 gene because the erythroblastic atypia is very similar to that found in neoplasms with a PCM-JAK2 junction (Giemsa ×150)

Blast crisis in PV is a late event and occurs only in a minority of patients (<10%). It is indicated by an increase of blasts above 19% either in the peripheral blood or the bone marrow. In most instances the blasts carry a myeloid phenotype, whereas lymphoid blasts crises are not encountered. Frequently, the blast crisis is accompanied by fibrosis which may precede transformation (Fig. 10). Megakaryocytes in these cases may be dysplastic and resemble those found in myelodysplastic syndrome (Fig. 10). In these cases only the record of a pre-existing polycythemic phase allows the diagnosis of a PV blast crisis (Fig. 10).
Fig. 10

Blast crisis in PV with more than 50% blasts and atypical megakaryocytes resembling those found in MDS. In cases like this, pre-existing PV is not obvious from histology and can only be diagnosed when PV is obvious from previous biopsies or clinical history (Giemsa ×250)

Immunophenotype

In the majority of cases, blast crisis in CML exhibits phenotypic markers of the myeloid lineage with a broad spectrum reaching from neutrophilic to monocytic, megakaryocytic, erythroid, basophilic, and rarely eosinophilic differentiation (Reid et al. 2009). Cells of blast crisis are frequently completely or partly negative for CD34 and CD117. Consequently, CD34 stain cannot be equaled with the blast content. When bone marrow fibrosis leads to dry tap, blast recognition in these cases rests on the histological attributes. In about a third of cases, blast crisis in CML is of lymphoblastic phenotype because the neoplastic cell of origin in CML belongs to the stem cell compartment or to a still uncommitted pool of early progenitor cells. Most lymphoblastic blast crises reveal a precursor B-cell phenotype and express terminal deoxynucleotidyl transferase in addition to B-lineage markers such as CD20, PAX5, and CD10. Rarely, a T cell phenotype is encountered. Probably as a consequence of their origin from an uncommitted precursor, cell pool blast populations commonly exhibit a mixed lineage phenotype with combined expression of myeloid and lymphoid markers (Khalidi et al. 1998).

In PV the blast crisis is usually myeloid with expression of corresponding markers (myeloperoxidase, lysozyme). Lymphoid markers may be co-expressed (mixed phenotype), but purely lymphoid blast populations are rare.

Molecular Features

Additional cytogenetic aberrations besides t(9;22) can regularly be observed in blast crisis of CML and occur in up to 90% of patients. Among the relevant aberrations are trisomy 8, doubling of the Philadelphia chromosome, isochromosome (17q), and trisomy 19 (Hehlmann et al. 2016). Additional chromosomal abnormalities may be present but are not considered to be of pathophysiological or prognostic relevance such as loss of the Y-chromosome and other rarer partial or complete chromosomal losses or gains. Chromosome 3 and 7 abnormalities can be detected during the course of the disease during chronic phase and have impact on prognosis and response to TKI (imatinib, dasatinib, nilotinib, bosutinib, ponatinib). Besides newly detectable chromosomal aberrations, acquired mutations appear to play a role in blastic progression. Mutations of the BCR-ABL tyrosine kinase are manifest in up to 80% of patients (Soverini et al. 2011). When ABL mutations occur during the chronic phase and induce imatinib resistance, the risk of blastic progression is markedly increased (Soverini et al. 2011). A variety of mutations which are usually found in MDS have been described in blast crisis such as RUNX-1, IKZF1 (Ikaros), ASXL1, WT1, TET2, IDH1, NRAS, KRAS, TP53, and CBL. Up to a quarter of all myeloid blast crises harbor alterations of the TP53 gene, whereas in lymphoid blast populations developing in CML, p16 aberrations prevail (Hehlmann et al. 2016).

Molecular findings have gained major impact on the definition of therapy resistance toward TKI. Usually, resistance is equaled with acceleration. Resistance can be either indicated by loss of complete hematologic response or loss of cytogenetic response. Quantitative polymerase chain reaction (PCR) products of reversely transcribed RNA from the BCR-ABL fusion gene in the peripheral blood is more and more used to monitor therapy response. Therapy resistance is diagnosed by rise of detectable BCR-ABL PCR products (b2a2 and/or b3a2 transcripts) and defined as loss of major molecular response. A reproducible fivefold increase in quantitative PCR is recommended as an early indicator of evolving therapy resistance and should prompt search for mutations of the ABL kinase and/or additional clonal chromosome abnormalities (Baccarani et al. 2014).

The molecular alterations underlying the various types of progression in PV (fibrotic, MDSMPN-like, blastic) are less well characterized when compared with CML. Almost all cases progressing to blast crisis exhibit karyotypic evolution, often with the acquisition of complex chromosomal abnormalities (Mesa et al. 2007). More than 98% of PV cases harbor a JAK2V617F or JAK2-exon 12 mutation. In a considerable proportion of cases, additional mutations such as of TET2 occur. It has been shown that the order of mutations in which they are acquired by the hematopoietic stem cell influences the clinical course of the disease (Ortmann et al. 2015). The impact of order in which mutations have been acquired has been demonstrated with regard to age of diagnosis, size of homozygous subclones, risk of thrombosis but not risk of progression. In blast crisis, JAK2-negative clones may emerge in a considerable proportion of cases (up to 50%). Additional MDS-like mutations such as TET2, DNMT3A, EZH2, and ASXL1 are associated with progression but appear not be newly acquired by the neoplastic clone with transformation but are already detectable during the chronic phase when signs of progression are not yet present (Lundberg et al. 2014). In those PV cases which later on progressed to myelofibrosis a higher proportion of double mutated (except TET2) cases were found when compared to non-progressing cases which proved to be only JAK2 or JAK2/TET2 mutated (Bartels et al. 2018). In this respect PV resembles primary myelofibrosis (Lehmann et al. 2013). An increase of JAK2 allelic burden was found by some investigators to be associated with fibrotic progression. This association could not be confirmed by others (Bartels et al. 2018). In a minority of PV cases with progression to MDS/MPN, a translocation of chromosome 9 involving the JAK2 gene occurs resulting in fusion of JAK2 with other genes and leading to a peculiar proliferation of erythroblastic islands (Fig. 9).

Differential Diagnosis

Progression in CML and PV either MDS/MPN-like or fibrotic has to be differentiated from the emergence of a second independent hematopoietic clone with a different clonal abnormality. A representative case is shown in Fig. 4, where increase of spleen size and worsening of blood cell counts suggested progression resulting in imatinib resistance of CML. Bone marrow biopsy in these cases reveal the emergence of a second independent clonal hematopoietic disease such as JAK2 positive MPN (Hussein et al. 2007). Unless previous biopsies from the pre-fibrotic phase are available, fibrotic PV cases are difficult to discriminate from primary myelofibrosis. In general, when bone marrow fibrosis grade 3 is present, it may be impossible to discern the underlying myeloproliferative neoplasm. The same is true for blast crisis. Up to 50% of blast crisis developing in JAK2-mutated MPN do not carry this mutation making it impossible to differentiate a secondary acute leukemia from an independent de novo AML. When the blast population has a lymphoid phenotype, other blastic lymphomas involving the bone marrow have to be differentiated.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Institute of Pathology Hannover Medical SchoolHannoverGermany