Secondary Leukemia (Sl)/Myelodysplasia (MDS) and Bone Marrow (BM) Chromosomal Aberrations after Dose-Intensive Chemotherapy for Neuroblastoma (NB).
Authors: Kushner Brian H. , Kramer Kim , Modak Shakeel , Jhanwar Suresh C. , Cheung Nai-Kong V. 
Published: October 2019

We previously described SL/MDS in 3/53 newly-diagnosed NB patients (pts) who received 4 cycles of high-dose cyclophosphamide (4200 mg/m2)-doxorubicin (75 mg/m2)-vincristine (CAV) and 3 cycles of high-dose cisplatin (200 mg/m2)-etoposide (600 mg/m2) (P/E), ± local radiotherapy (RT), ± immunotherapy using the anti-GD2 3F8 antibody, ± targeted RT using 131-I-3F8. With longer follow-up and the addition of a further 11 pts who received 7 cycles and 5 pts who received 6 cycles, there are 3 more cases of SL/MDS (Table1), which gives SL or MDS in 6/69 pts.

Table 1. Pts with Secondary Leukemia or MDS

Age From Dx Presentation Type Cytogenetics * all 3 received 7 cycles; 2 also received local RT and 3F8 ** all 3 received 7 cycles, local RT, 3F8, and 131-I-3F8 Previously reported cases (J Clin Oncol16:3880, 1998)* 4y 15m surveillance BM M2 del(9)(q13q34),del(11)(q23q25) 5y 27m thrombocytopenia MDS del(5)(q11), der(7)t(7;17)(q11,q11), −17 12y 7m monocytosis M5 del(11)(q23) (rearranged MLL gene) New cases** 3y 12m leukocytosis ALL t(4;11)(q21;q23) (rearranged MLL) 8y 50m thrombocytopenia MDS del(5q) and del(7q) 25y 24m thrombocytopenia MDS del(7q)

This SL risk was a reason for subsequently limiting induction to 3 CAV and 2 P/E. At 4+-to-72+ months (median, 19+), SL/MDS has not occurred in 46 pts treated with 5 cycles, including 19 who received thiotepa-topotecan-carboplatin (TTC) with an autologous stem-cell transplant and 11 who received both TTC and oral etoposide (E) maintenance.

In routine surveillance studies, 4 pts in the 6/7-cycle group had BM cytogenetic changes (worrisome for SL) that spontaneously resolved, and 1 pt in the 5-cycle group had a cytogenetic aberration that has persisted in >90% of BM cells for 15+ months, without morphologic or clinical evidence of SL/MDS (Table 2). Allo-transplant was recommended, but not done, for this patient and for the 10 yr old with a t(3;6) translocation that was documented in 20%-to-100% of BM mitoses for 26 months before finally disappearing (Table 2).

Table 2. Pts with chromosomal aberrations but no SL or MDS

Age From Dx # of Cycles, other Rx* Cytogenetics, Duration * all of these pts also received 3F8 18y 10m 7, local RT inv(11)(q21q23) (rearranged MLL), 1m 6y 21m 7, local RT, 131-I-3F8 t(2;16)(q31;q22) t(6;10)(q21;p13), 4m 10y 22m 6, local RT, 131-I-3F8 der(6) t(3,6)(q23, p25), 26m 6y 24m 7, local RT, 131-I-3F8 dup(1)(q21q32), 14m 5y 17m 5, local RT, TTC, oral E t(4;11)(p12;q23) (rearranged MLL), 15m+

In prior-treated NB pts, we also found transient BM cytogenetic abnormalities, some associated with leukemia or MDS, including del(16) (q22) and del(7q), though others are not, including inv(17) (p13q23).

We conclude that fewer cycles of dose-intensive induction may reduce risks of SL/MDS and that BM cytogenetic abnormalities do not invariably evolve into SL or MDS. The nature of other genetic or epigenetic abnormalities that underlie such a transformation is currently unknown.