Intensified therapy for infants with acute lymphoblastic leukemia

Abstract

We read with great interest the report by Silverman et al.1 summarizing treatment outcome in 23 infants treated with Dana-Farber Cancer Institute Consortium protocols. Intensified multidrug therapy resulted in significantly improved long term, event free survival in 54% ± 11% of infants. This included at least three patients with MLL gene rearrangements, which are known to be associated with multidrug-resistant disease. The authors describe two infants in whom the blasts at the time of recurrence differed phenotypically from those at diagnosis. They considered the possibility of secondary leukemia, but also speculated about recurrence of the leukemia with a phenotypic shift. In our opinion, the latter explanation appears most probable. In acute lymphoblastic leukemia (ALL) occurring in infants, particularly in cases with MLL gene rearrangements, leukemogenesis affects early progenitor cells. In such patients cross-lineage expression of myeloid antigens such as CD13, CD15, CD33, and CD65 frequently is observed,2 in a minority of cases even biphenotypic acute leukemia has been diagnosed based on simultaneous expression of lineage specific antigens.3 Using clone specific markers such as clonal immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements, it is possible to distinguish between recurrence and secondary, therapy-related leukemia. We previously described a pre-B-ALL patient who developed acute myeloid leukemia 17 months after diagnosis, suggesting the development of secondary leukemia. However, the Ig and TCR gene rearrangement pattern was identical between diagnosis and recurrence, implying cytomorphologic and immunophenotypic evolution of the same clone.4 In contrast to previous reports,3 Silverman et al.1 clearly showed that infant ALL in principle can be cured. However, 50% of patients still recur. This implies that analysis of specimens at diagnosis is not sufficient for predicting treatment response and that more insight is needed into in vivo effectiveness of treatment during the follow-up. This is possible with the currently available standardized techniques for the detection of minimal residual disease (MRD).5 To exemplify this strategy we show the monitoring of MRD in a 10-month-old infant with common ALL using a patient specific oligonucleotide probe to the junctional region of an IGK gene rearrangement (Fig. 1 (178k)).6 Despite cytomorphologic remission at the end of induction therapy, we still could detect low levels of malignant cells. The recurrence 14 months after diagnosis was predicted 3 months earlier with molecular MRD analysis. We believe that such prospective MRD monitoring can be used for the assessment of treatment response and can be applied toward individualization of therapy to improve the outcome of infant leukemia further. VκVII and Kde primers were used for polymerase chain reaction (PCR) amplification of bone marrow DNA samples at diagnosis (D) as well as during follow-up. The PCR products were spotted onto a nylon membrane, which was hybridized with the 32P-labeled junctional region probe. Tenfold dilution series of diagnosis DNA revealed a sensitivity of 10-4 (one acute lymphoblastic leukemia cell between 104 normal cells). During follow-up the bone marrow became negative after Week 15, but at Week 47 PCR positivity was found again (i.e., 3 months before clinical recurrence [R]). bp: base pairs; MNC: DNA from normal mononuclear cells. Tomasz Szczepański M.D.*