Poor treatment responses were related to poor outcomes in pediatric B cell acute lymphoblastic leukemia with KMT2A rearrangements

Abstract

Background The KMT2A gene, formerly named the MLL gene, is rearranged (KMT2Ar) in 70–75% of infants, 5–6% of children and 10–15% of adult patients with B cell acute lymphoblastic leukemia (B-ALL). The outcome after chemotherapy of pediatric cases remains poor, and only a few studies have investigated the clinical and laboratory features, treatment response and prognosis in Chinese populations. Methods A total of 48 B-ALL children with KMT2Ar were enrolled in the study, and clinical and laboratory data were collected and analyzed by age group. The relationship between prognosis and traditional risk factors and treatment response was investigated for these patients who received chemotherapy. Results The 48 enrolled patients included 28 males and 20 females; 18 (37.50%) or 30 (62.50%) patients were an age of < 12 m (infant B-ALL) or of > 12 m at onset. An initial WBC count of 300 × 109/L was detected in 7 (14.58%) patients; testicular leukemia (TL) or central nervous system involvement was found in 5 (10.41%) or 3 (6.25%) patients, respectively. Statistical differences were not found in the age groups of sex or initial WBC count, whereas TL was more common in the infant group (P < 0.05). 11q23 was detected in 18 patients; KMT2Ar was detected in 46 (95.83%) or 45 (93.75%) patients by FISH or multiplex RT–PCR technology, respectively; RNA-seq data were obtained for 18 patients, and 3 patients with uncommon KMT2Ar were identified. KMT2A-AFF1, KMT2A-MLLT3 and KMT2A-MLLT1 were the most common transcripts. Statistical differences were not found in treatment response by age groups, including dexamethasone induction, bone marrow (BM) smear status and minimal residual disease (MRD) level at different time points (TP), treatment-related mortality (TRM), or complete remission (CR) rate (P > 0.05); MRD levels monitored by FCM or PCR were unequal at the same TP. Four patients died of treatment, and TRM was 8.33%; 40 patients achieved CR, and the CR rate for the cohort was 83.33%. Seven patients quit, 15 patients relapsed, and the 5 yr cumulative relapse rate was 59.16 ± 9.16%; the 5 yr prospective EFS (pEFS) for patients who were included or excluded from the TRM group was 36.86 ± 8.48% or 40.84 ± 9.16%, respectively. Multivariate analysis for prognosis and hazard ratio was performed for 37 patients without TRM and revealed that an initial WBC count of > 300 × 109/L and a positive level of FCM-MRD were strongly related to a poor outcome for B-ALL patients with KMT2Ar (P < 0.05).

Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation

“…In fact, the KOPN-8 cell line presents the chromosomal translocation (11;19)(q23;p13) that encodes for KMT2A-MLLT1 (also known as MLL-MLLT1 or MLL-ENL ) fusion gene [ 24 ]. KMT2A encodes for a histone methyltransferase involved in epigenetic regulation of blood cell development, and its deregulation is associated with leukemia initiation [ 3 , 37 ]. This translocation and all other rearrangements involving KMT2A are strongly associated with a poor treatment outcome in B-ALL young patients [ 37 ].…”

“…KMT2A encodes for a histone methyltransferase involved in epigenetic regulation of blood cell development, and its deregulation is associated with leukemia initiation [ 3 , 37 ]. This translocation and all other rearrangements involving KMT2A are strongly associated with a poor treatment outcome in B-ALL young patients [ 37 ]. Recently, in a study focused on its anti-inflammatory effects, a brusatol derivative was shown to inhibit the spleen tyrosine kinase (SYK) [ 38 ], a kinase whose constitutive activation and associated signaling inhibition was already demonstrated in B-ALL with KMT2A rearrangements [ 39 ].…”

The Relevance of Telomerase and Telomere-Associated Proteins in B-Acute Lymphoblastic Leukemia

“…In addition, there are other known rearrangements involving KMT2A , such as KMT2A-AF10, KMT2A-AF9, and KMT2A-ENL [ 37 , 38 , 39 ]. These chromosomal rearrangements produce oncofusion proteins that harm the differentiation of hematopoietic stem cells [ 40 ]. The KMT2A-AFF1 translocations arise in utero and rapidly lead to the development of overt ALL.…”

Updates in KMT2A Gene Rearrangement in Pediatric Acute Lymphoblastic Leukemia

“…A very poor prognosis relates to a median survival rate of less than 12 months (as in the case of KMT2A::MLLT1 fusion) [ 32 ]. Poor prognosis refers to a median survival rate of 12 to 60 months [ 33 , 34 , 35 , 36 ]. KMT2A :: MLLT3 fusion manifests an intermediate prognosis in the case of AML with other KMT2A translocations [ 37 ].…”

“…The median follow-up time for the 37 patients without TRM was 15.48 months, 15 patients relapsed, and the 5-year cumulative relapse rate for the 37 patients was 59.16 ± 9.16%. For patients with TRM on (41 patients) or TRM off (37 patients), the 5-year prospective EFS (pEFS) was 36.86 ± 8.48% or 40.84 ± 9.16%, respectively [ 33 ].…”