In this report, we have summarized our experience and reviewed the published literature on SM that coexists with t(8;21)(q22;q22) AML. KIT
mutations are the most common additional genetic abnormality in t(8;21) AML and range in their incidence from 26% to 47% in various reports [22
]. However, among the t(8;21) AML with KIT
mutations, the number of cases that have concurrent SM appears to be extremely rare. Hence, it appears that specific genetic events in addition to activating KIT
mutations and t(8;21) are required for development of mastocytosis. Although it can be postulated that these additional genetic events may promote mast cell differentiation from leukemic progenitors, the nature of these additional genetic aberrations remains unknown.
Studies examining the relationship between mast cells and leukemic blasts have shown that the neoplastic mast cells of SM associated with t(8;21) carry the RUNX1-RUNX1T1
translocation, thereby proving their derivation from the leukemic clone. This was demonstrated in case 3 of this series by target FISH, the details of which have been published elsewhere [21
]. Similar findings were noted in another published case that is included in the current series (case 10, Nagai et al.) where KIT
mutation as well as RUNX1-RUNX1T1
translocation was detected in recipient-derived clonal mast cells that persisted after allogeneic HSCT [20
]. In both these cases, the recipient-derived mast cells gradually declined and the AML remained in remission. It is unclear if this phenomenon represents gradual apoptosis of these mast cells or progressive elimination of leukemic progenitors due to graft-versus-leukemia effect.
We sought to examine if there were other distinct cytogenetic or pathologic features that were associated with SM and t(8;21) AML. Deletion of chromosome 9q was an additional cytogenetic finding in four of the ten cases. Del (9q) has been previously reported as part of a complex phenotype in another case of t(8;21) positive myelomastocytic leukemia (AML with increased bone marrow mast cells not meeting criteria for SM) [26
]. In addition, del (9q) is the most common additional cytogenetic abnormality in t(8;21) AML and has been reported in 7–14% of pediatric cases and 9.7% of adult cases [27
]. In comparison, del (9q) appears to be more frequent in t(8;21) with associated SM, suggesting that this deletion may play a role in the pathogenesis of SM. Recently, TLE1
have been identified as critical genes in the commonly deleted 9q region in t(8;21) AML [28
]. In vitro experiments using Kasumi-1 cell line showed that these genes behave as tumor suppressors and knockdown of TLE1
increased the rate of cell division of the AML1-ETO
expressing Kasumi-1 cell line while forced expression of either caused apoptosis and cell death [28
The precise incidence of SM coexisting with t(8;21) AML is unknown. In previous reports, authors have cautioned that in some cases of AML with coexisting SM, the diagnosis of SM maybe missed on the initial bone marrow evaluation due to the excess numbers of blasts which mask the underlying mast cells and the tendency of mast cells to localize within stroma of bone marrow particles in aspirate smears [9
]. The bone marrow mast cell infiltrate appears to become more evident when the leukemic blasts decrease after therapy as was seen in this report (Fig. b). This prominence of the mast cell infiltrate after chemotherapy may also be due to the poor sensitivity of the mast cells to leukemia chemotherapy as evidenced by their persistence even after high-dose chemotherapy conditioning for allogeneic HSCT [20
]. Infiltration of extramedullary tissues with mast cells, as well as symptoms due to mast cell mediator release, appear to be distinctly uncommon in cases of SM associated with t(8;21) AML. This may be due to the lack of functionality of these neoplastic MC as a result of the leukemic aberrations they carry.
AML with t(8;21)(q22;q22) as the sole cytogenetic abnormality in general have a favorable outcome when treated with consolidation regimens containing high-dose cytarabine [29
]; however, studies have shown that only 50% of t(8;21) AML patients are alive at 5 years [27
]. D816 KIT
mutations were detected in 10.5% of patients with t(8;21) AML in one study [17
]. The presence of KIT
mutations (D816 and others) may explain the poor prognosis of a subset of t(8;21) patients as activating exon 17 KIT
mutations have now been shown to be a major adverse prognostic factor for event-free and overall survival in t(8;21) AML [14
] and a predictor of higher relapse risk [15
]. The number of patients with mutant KIT
who had SM in addition has not been reported in any of these studies, which may be an indicator of its extreme rarity. Interestingly, in previous studies it has been reported that 91–100% of t(8;21) AML patients with KIT
mutations achieved complete remission after chemotherapy [15
]. However, in our current series induction failure occurred in four of ten patients. This observation again re-emphasizes the fact that SM associated with AML has a grave prognosis.
It is worth noting that of the ten patients (Table ) only two patients achieved a durable remission of AML. Both of these patients had undergone allogeneic HSCT. One of our patients (case 3) is in continuous remission 4 years after allogeneic HSCT. Sperr et al. have reported a patient with myelomastocytic leukemia and t(8;21) AML who relapsed after a reduced intensity HSCT, but achieved a lasting remission following high-dose conditioning and a second HSCT from the same donor, thereby suggesting that conditioning intensity may be important [26
]. Although data are very limited, the dismal results with conventional chemotherapy suggests that allogeneic HSCT should be an early consideration in SM associated with t(8;21) AML in patients who are suitable candidates. The D816V KIT
mutation is resistant to the tyrosine kinase inhibitor imatinib [31
]. Dasatinib, to which KIT
D816V is sensitive, may have a role in the therapy of these cases as evidenced by in vitro data as well as its in vivo activity of this drug in recent reports of SM, including a patient with SM-AML [32
]. Other tyrosine kinase inhibitors like midostaurin (PKC 412) and nilotinib (AMN 107)) that are capable of inhibiting activating KIT
D816V may also have potential in the treatment of t(8;21) AML that carry this mutation [35
In conclusion, SM associated with t(8;21) AML is extremely rare and carries a dismal prognosis. During evaluation of t(8;21)(q22;q22) AML, care should be taken to look for coexisting SM in the initial and subsequent bone marrow specimens since the mast cell infiltrate may be subtle and easily overlooked. This will help identify a subset of t(8;21) AML patients with a particularly poor prognosis.