The chapter considers specific treatment options, including allogeneic hematopoietic stem cell transplantation (allo‐HSCT) in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), in patients with some prognostically proven cytogenetic variants as monosomal ones, complex and hyperdiploid karyotypes, like chromosomal translocations t(v;11)(v;q23), t(3;3)/inv(3); t(8;21), t(9;22), etc. Important prognostic role of additional chromosome abnormalities was shown for the patients with t(8;21) and t(9;22). Hence, it is evident that allo‐HSCT in patients with poor risk cytogenetic variant must be performed as early as possible, i.e., during first complete remission.
- cytogenetic abnormalities
Acute leukemias represent a mixed group of malignant diseases with heterogeneous morphology, cytogenetics, and prognosis. From a genetic point of view, acute myeloid leukemias (AML) and acute lymphoblastic leukemias (ALL) consist of patients with favorable‐, intermediate‐, and poor‐risk cytogenetic variants. A group of AML patients with favorable cytogenetics traits include those with translocations t(15;17), inv(16)/t(16;16), and t(8;21), whereas t(12;21) and high hyperdiploid karyotypes are associated with better prognosis in ALL patients. Currently, the group of AML patients with poor‐risk cytogenetics includes cases with ‐7/7q‐, ‐5/5q‐, ‐17/17p‐, t(3;3), t(6;9), t(v;11)(v;q23), monosomal, and complex karyotypes, whereas those with ALL exhibit mainly t(4;11) and t(9;22). Since a great part of AML and ALL patients are not cured by single chemotherapy, they need allogeneic hematopoietic stem cell transplantation (allo‐HSCT). So far, the results of allo‐HSCT in patients with poor‐risk and favorable‐risk leukemias were analyzed in common cohorts [1, 2]. The aim of our work is to compare clinical outcomes of allo‐HSCT for the patients with distinct cytogenetic variants.
2. Acute myeloid leukemia
2.1. AML with monosomal karyotype
One of the poor‐risk chromosome abnormalities in AML patients is monosomal karyotype (MK), which is defined by the presence of one single autosomal monosomy in association with, at least, one additional autosomal monosomy or one structural chromosomal abnormality except for marker and ring chromosomes (Figure 1). MK is associated with a dismal prognosis and seems to be prognostically important even in complex karyotype AML. Breems et al.  were the first who have noted clinical significance of this finding. More recently, a strong association with
2.2. AML with complex karyotype
The interest to AML with CK as a distinct biological entity has appeared recently [7–11]. This anomaly is defined as three and more structural and numerical chromosome aberrations per metaphase (Figure 1), when excluding such recurring abnormalities, as t(8;21), inv(16)/t(16;16), t(15;17), or 11q23/MLL rearrangements [11–14]. Nowadays, it accounts for 10–20% of AML cases and increases sharply with age . Despite intensive treatment, including allo‐HSCT, median OS for these patients was <6 months and less than 10% patients achieved long‐term survival . It has been also established that incidence of CK+ cases in AML may increase after chemotherapy  and HSCT [18–20]. However, some recent data  suggested that a 90% CR rate was achieved for these poor‐risk patients, if allo‐HSCT was performed within 80–100 days after diagnosis even in active phase of the disease. A hypothetic explanation is that poor prognosis of AML patients with CK may be associated with a chromosomal instability which, in turn, is directly related to clonal evolution, selection, and adaptation of leukemic cells .
2.3. AML with hyperdiploid karyotype
Patients with hyperdiploid karyotypes (HDK) are not so rare in AML too, revealing many in common with aforementioned CK (Figure 2). For instance, in cases of sole chromosomes 8, 21, and 13 trisomies, these cases are classified as intermediate risk group. On the other hand, a new heterogeneous group with high hyperdiploidy and modal chromosome numbers from 49 to 65 has been recently described in about 2% of poor‐risk AML patients , which was prognostically poor. Finally, cases with near triploid/tetraploid karyotype, especially associated with structural chromosome anomalies are encountered not so often [23, 24]. Since there are no available publications concerning of allo‐HSCT results in AML patients with HDK, we presented here our data on the topic in details . Study group enrolled 47 AML patients (21 females, 26 males, aged 1–58 years; median age 23.9 years), in whom allo‐HSCT was performed at our university during 2008–2015 years. Cytogenetic evaluation included standard GTG differential staining of chromosomes as well as Multicolor FISH (M‐FISH), which were carried out according to standard manufacturer recommendations. Criteria for defining aberrations and nomenclature for description of the cytogenetic findings were in accordance to the international system for human cytogenetic nomenclature (ISCN) . Allo‐HSCT was performed in 13/47 (28%) patients in the first complete remission (CR), in 7/47 (15%) patients in the second CR, whereas 27/47 (57%) patients were transplanted in active disease. Sources of stem cells for the patients were as follows: bone marrow (n = 23; 49%) or peripheral blood stem cells (
2.4. AML with
KMT2A (MLL) rearrangement
AML with 11q23/
2.5. AML with t(3;3)(q21;q26.2)/inv(3)(q21q26.2)
AML with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a distinct subtype of AML with recurrent genetic abnormalities. It is commonly refractory to conventional chemotherapy due to
2.6. AML with t(8;21)(q22;q22)
RUNX1/RUNX1T1, inv(16)(p13q22)/t(16;16) CBFβ/MYH11
In view of the data concerning poor‐risk AML groups, it would be interesting to discuss clinical outcomes after allo‐HSCT in cohorts with favorable‐risk cytogenetics. Several such studies should be mentioned [37–39]. The data revealed by Yoon et al.  consist of 264 adult patients with CBF‐positive AML, where 206 of whom were in CR. Allo‐HSCT was performed in 115 patients, whereas other patients were treated either by auto‐HSCT (
3. Acute lymphoblastic leukemia
3.1. ALL with translocation t(9;22)(q34;q11.2)
Philadelphia‐positive acute lymphoblastic leukemia (Ph+ ALL) has been regarded for decades as the ALL subgroup with inferior outcome. However, introduction of tyrosine kinase inhibitors (TKI) in the induction treatment provided complete hematologic remissions (CHRs) in nearly all patients [44–51], thus allowing to recommend them as gold for Ph+ ALL patient’s treatment. Together, these findings show that complete response to the therapy, including molecular remission, were achieved earlier in TKI‐treated cohorts of ALL patients, whereas OS and DFS in these patients lasted longer than in a cohort that avoided TKI, regardless of their combinations with auto‐ or allo‐HSCT. It has been also noticed that additional chromosome aberrations may be a poor predictor for the treatment results . Three‐year leukemia‐free survival (79.8% vs. 39.5%,
3.2. ALL patients with
KMT2A (MLL) gene rearrangements
Structural rearrangements of 11q23.3 caused by inducing exchanges of
Analysis of the HSCT results in patients with prognostically different cytogenetic variants of acute leukemias showed that this approach may be efficient in all the tested patients and that it can be effective enough in all tested cohorts, including patients with the most poor‐risk leukemias with monosomal and complex karyotypes, as well as those with translocations t(4;11)(q21;q23), t(9;22)(q34;q11.1), t(3;3)(q21;q26.2), etc. The situation can be dramatically changed with the introduction of highly effective targeted drugs, e.g., TKIs, into therapeutic protocols for Ph‐positive leukemias.
The authors would like to acknowledge the assistance of Professor Alexei Chukhlovin in the preparation of this manuscript.
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