Mixed lineage leukemias

MIXED LINEAGE LEUKEMIAS / HYBRID LEUKEMIAS

Epidemiology : biphenotypic acute leukemias may affect adults or children, particularly infants under 2 years old.
It is likely that the cases referred to as myeloid antigen-positive acute lymphoblastic leukemia (My⁺ ALL) and lymphoid antigen-positive acute myeloid leukemia (Ly⁺ AML) include a miscellaneous group that encompasses true biphenotypic leukemias as well as others which are ALL or AML with atypical expression of a single marker from another lineage.

biphenotypic leukemia : myeloid and lymphoid markers on the same cell clone
bilineage or biclonal acute leukemia (BAL) (4-8% of all acute leukemias) : different clones in the same patient

mixed acute lymphoblastic leukemia (ALL)
mixed prolymphocytic leukemia

B-PLL and T-PLL
CD4⁺ & CD8⁺ T cells in T-PLL

mixed CLL : B-CLL and T-CLL
B and T lymphoid markers (very uncommon)
bilineage acute leukemia : often AML M1 or M2

myeloid-B-cell leukemia (most common)
myeloid-T-cell leukemia (less common)
myeloid-natural killer cell leukemia

phenotypic switch

AML => ALL^ref with unrearranged IgH genes^ref
B-ALL => AML^ref with same IgH rearrangement^ref
Ph+ B-ALL^ref => MDS => AML with unchanged cytogenetic findings, making unlikely t-MDS/t-AML^ref
Ph+ B-ALL => Ph+ AML M2^ref
pro-B ALL with a minor myeloid component at diagnosis to minimally differentiated acute myeloid leukemia (AML); Ph+ early T-cell ALL with minor myeloid component ^ref
congenital B-ALL with t(4;11) and t(1;6) translocations (MLL gene rearrangement) => monocytic lineage with persistence of the original cytogenetic translocations and clonal rearrangement of the J_H gene and followed an aggressive clinical course^ref.
CD4^-7⁺8^- T-ALL => AML^ref
Ph⁺ (m-bcr, e1a2) AML (a rare and heterogeneous condition, mainly reported in adults, associated to poor prognosis and unfavorable response to therapy) with myeloid (FAB M4) morphology a mixed, myeloid-lymphoid lineage => full lymphoid phenotype following allogeneic stem cell transplants, in association with an immature B-cell gene rearrangement profile and clonal instability during clinical progression. This report indicates a stem cell origin as previously suggested for Ph+ AML^ref.
Ph⁺T-ALL and acute myelomonocytic leukemia. Chromosome analysis showed 46,XY,del(7)(p11.2),t(9;22)(q34;q11.2) in all metaphases and a minor BCR/ABL chimeric gene was detected in these leukemic cells by PT-PCR. When the CD5⁺ and CD5^- cells were sorted, a fusion gene of BCR/ABL and the same clonally rearranged band of a TCR gene were detected in both populations. Nucleotide sequencing of the TCR-g gene revealed the clonal rearrangement of the Vg8-JGT2 complex in both populations. Overexpression of PU.1, which plays a fundamental role in myelomonocyte development, was found in the sorted CD34⁺CD7⁺ and CD5^-, but not CD5⁺ cells. These results suggest that leukemic progenitor cells in the T-lineage with the del(7) and t(9;22) have the potential to differentiate into myeloid lineage, and that enforced PU.1 expression may contribute in part of this phenomenon^ref

Clonality switch

^ref

trilineage or triphenotypic acute leukemia / AML with myelodysplasia : > 25% abnormal erythroid cells OR > 50% abnormal granulocytes or megakaryocytes (usually classified as AML M2, rarely as M6 or M7)

myeloid, B-, and T leukemia (rare)
myeloid, B-, and natural killer cell leukemia : rearrangement of IgH-chain gene and absence of EBV DNA^ref

A scoring system has been proposed aimed at distinguishing cases of bona fide biphenotypic acute leukemia from those with aberrant expression of a marker from another lineage, eg. Ly⁺AML and My⁺ALL. This system is based on the number and degree of specificity of the markers (lymphoid and myeloid) expressed by the leukemic cells^ref. The table below shows the markers regarded as most specific as follows :

for the B-lymphoid lineage, CD79a (mb-1) detects a transmembrane protein linked to the immunoglobulin which constitutes part of the receptor for antigen recognition in B lymphocytes, cytoplasmic immunoglobulin and CD22
for the T-lymphoid lineage, CD3 linked to the TcR complex and expressed in the cytoplasm early in T cell development
for the myeloid lineage, myeloperoxidase (MPO) detected either by conventional cytochemistry or with a monoclonal antibody against the a-chain of MPO and the proenzyme form.

Scoring system for the definition of acute biphenotypic leukemias. Biphenotypic acute leukemia is established when the score from 2 separate lineages is > 2.

scoring points	lineages
	B-lymphoid	T-lymphoid	myeloid
2	CD79a (mb-1) CD22 cyt IgM	cyCD3 > sCD3 (TcRb)	MPO (demonstrated by cytochemical or immunological methods)
1	CD19 CD10 CD20	CD2 CD5	CD13 CD33 CD65
0.5	TdT CD24	TdT CD7 CD1a	CD11b CD11c, CD14 CD15 CD64 CD117

According to this scoring system, a case is considered biphenotypic when point values are > 2 for the myeloid and 1 of the lymphoid lineages. Cases involving both lymphoid lineages (B and T) are very rare; cases with markers for the 3 lineages (triphenotypic) are also rare. It is likely that in the future other markers with a high degree of lineage specificity will be incorporated into the scoring system, for instance markers recognizing the a/b and g/d chains of the TcR for the T-lymphoid lineage or CD117 (c-kit), which seems to be specific for myeloid cells. Some of these markers are currently being evaluated by the EGIL group.

morphology and cytochemistry : in 33% of the cases, the blasts resemble lymphoblasts (L1 or L2 morphology). Cytochemical staining with Sudan black B (SBB), MPO and a-naphthyl acetate-esterase (ANAE) are negative (< 3%+ blasts). The remaining cases can be classified as AML on the basis of standard morphology and cytochemistry because they show > 3% blasts positive with SBB or MPO, or display a pattern of ANAE activity typical of monoblasts (diffuse, strong and sensitive to NaF). According to FAB criteria most of the latter cases are either M1 or M2 or, rarely, M4 and M5. We have not yet seen a case with biphenotypic features which corresponds to the M3, M6 or M7 subtypes. It is not unusual to identify 2 distinct blast populations in the same patient, one of small size with a high nucleus/cytoplasm ratio resembling lymphoblasts and the other larger with more abundant cytoplasm with or without granulation. Despite these distinct morphological features, there is nearly always a clear overlap in the expression of lymphoid and myeloid markers in both types of cells
immunological markers : most cases are terminal deoxynucleotidyl transferase (TdT) positive and express early hemopoietic markers such as CD34 and class-II HLA-DR determinants. In cases of biphenotypic acute leukemia classified as ALL by light microscopy morphology and cytochemistry (SBB^–, MPO^–), MPO activity can be demonstrated using sensitive techniques on unfixed cells at the ultrastructural level (Matutes E, Buccheri V, Morilla R, Shetty V, Dyer M, Catovsky D. Immunological, ultrastructural and molecular features of unclassifiable acute leukemia. In: Ludwig WD, Thiel E, eds. Recent advances in cell biology of acute leukaemia. Berlin:Springer, 1993:41-52) or with the anti- MPO monoclonal antibody^ref. These findings support the myeloid commitment of the blasts. The fact that MPO activity cannot be detected by light microscopy cytochemistry is related to the small amount of this enzyme, which is only seen by electron microscopy in very small granules and in cell membranes. Alternatively, it is possible that the blasts contain the enzyme as a proenzyme form, which nevertheless is detectable with the monoclonal antibody. In cases of biphenotypic acute leukemia presenting with morphological and cytochemical features of AML, there is a high incidence (50%) of rearrangement of the IgH chain gene and/or TcR chain genes, further confirming the lymphoid commitment of the blasts at a genomic level (simultaneously with the myeloid features)^ref
cytogenetics : there is no single chromosomal abnormality which is uniquely associated with biphenotypic acute leukemia. Our own data and those of others demonstrate that structural chromosome abnormalities are frequent and that there is a high incidence of the Philadelphia chromosome t(9;22)^ref, seen in one third of the cases, rearrangements involving 11q23 and complex cytogenetic abnormalities^ref

Symptoms & signs : they may present as de novo or, rarely, they become apparent during a relapse following anti-AML or ALL therapy. The WBC is often high and most cases have a varying proportion of circulating blasts (Zomas A, Modak S, Pinkerton R, et al. Childhood biphenotypic leukaemia: six-year experience from a single centre [abstract]. Br J Haematol 1995; 90:67.)
Therapy : there are no uniform criteria about whether to treat these cases as ALL or AML when they are diagnosed only by standard morphology and cytochemistry, or whether to use an approach which combines drugs that are effective for ALL and AML^ref, followed by bone marrow or mobilized peripheral stem cell transplantation in complete remission^ref.
Prognosis : extensive data on response to therapy and clinical outcome are not available; however, our impression based on cases treated at the RMH and from single cases reported in the literature is that of a poor outcome in both children and adults. This may be related to the underlying chromosome abnormality^ref.
Differential diagnosis :

lineage infidelity :
antigenc asynchrony
antigenic absence
antigenic intensity anomalies

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