Children With Ambiguous Leukemia Fare Better With Lymphoid-Directed Treatment

While most patients with acute leukemia have disease with a lymphoid or myeloid linage, 2 to 5 percent have “acute leukemia of ambiguous lineage” (ALAL), expressing features of both lymphoid and myeloid lineage. Given the rarity and heterogeneity of this disease subtype, there are no standard treatment recommendations for these patients. In a retrospective study published in Blood, researchers collected data on the biologic features, treatment, and outcome of 233 children with ALAL and were able to outline treatment algorithms that can be tested in prospective trials.

“[This is] the largest study to date on childhood ALAL,” wrote the authors, led by Ondrej Hrusak, MD, PhD, of the Department of Pediatric Hematology/Oncology at Charles University in Prague. Their analysis “[revealed] a better prognosis of children who started on lymphoiddirected treatment, [while] myeloid type of primary treatment correlated with dismal outcomes in [those with] CD19-positive leukemias.” The multicenter, international study included data from children who were diagnosed with acute leukemia between 2002 and 2015 and treated at one of 18 international centers. Of the 233 eligible patients:

  • 176 had single-population ALAL (a single population of leukemic blasts co-expressing both lymphoid and myeloid lineages)

  • 45 had bilineal leukemia (more than one population of leukemic blasts expressing a single lineage)

  • 12 had undifferentiated leukemia (blasts expressing neither lymphoid or myeloid lineages)

Primary treatment protocols included:

  • acute lymphocytic leukemia (ALL)–type therapy (n=148)

  • acute myeloid leukemia (AML)– type therapy (n=60)

  • combined therapy (n=25)

“Given that the phenotype of ALAL is in between classical ALL and AML, it has always been tempting to speculate that these leukemias would respond best to therapy which would comprise elements of both ALL and AML types of treatment,” the authors wrote. “This speculation assumes that what has been proven empirically for ‘pure’ ALL or AML would analogically hold true for borderline cases.”

According to their findings, this assumption is incorrect: In addition to the poorer results seen with myeloid-directed treatment, “both ALL- and AML-types of treatment are close to maximum tolerable intensity, [so] by intending to combine these treatments, we either compromise their efficacy or increase the risk of toxicity beyond acceptable margins.”

Treatment-related toxicity was “relatively high,” according to the researchers, accounting for 18 of 63 on-study deaths, but appeared to be distributed evenly between ALL-type, AML-type, and combined-therapy cohorts (7.4%, 8.3%, and 8%, respectively).

Patients who initiated lymphoid-directed treatment had greater rates of five-year event-free survival (EFS; 80±4.0%), compared with those who initiated either myeloid-directed treatment (36±7.2%) or combination treatment (50±12%; p values not reported).

Bilineal ALAL (in which two separate clones of different lineages coexist) also was associated with better five-year EFS when treated with lymphoiddirected therapy (65±12%), compared with myeloid-directed therapy (14±13%; p values not reported); however, patients with this subtype fared worse with these treatments than those with single-population ALAL (84±4.2% with lymphoid-directed vs. 43±8.9% with myeloid-directed therapy).

“The spectrum of underlying genetic aberrations is wide [in ALAL],” the researchers noted, and the presence of these mutations did not appear to correlate with prognosis. In 202 patients without typical leukemia-associated mutations (including ETV6/RUNX1, TCF3/ PBX1, RUNX1/RUNX1T1, PML/RARA, or CBFB/MYH11), outcomes were similar, except among patients with CD19-positive disease.

In this group, five-year EFS was strongly correlated with treatment type: 83±5.3% for ALL-type treatment versus 0% for AML-type treatment and 28±14% for combined therapy (p<0.0001 for both). “The striking failure of AML-type therapy to cure any child with CD19-positive leukemia in the absence of AML-specific gene fusions leads us to recommend other types of chemotherapy in this relatively large subset of ALAL,” the authors noted.

Rarely, when ALAL presented without expression of CD19 (n=67), the outcomes were poor, especially with ALL-type treatment, “making [combined and AMLtype] treatment preferred,” they added.

Analyzing these collective data, the authors proposed the following primary treatment algorithm for patients with ALAL:

  • Treat as ALL if molecular genetics or cytogenetics reveal a BCR/ABL1, ETV6/RUNX1, TCF3/PBX1 mutation or CD19 positivity.

  • Treat as AML if molecular genetics or cytogenetics reveal a RUNX1/RUNX1T1, PML/RARA, or CBFB/ MYH11 mutation.

  • Treat as AML or combined type if disease shows none of these mutations; is CD19-negative; or is CD3-, CD7-, or CD22-positive.

The benefit of hematopoietic cell transplantation (HCT) with this disease subtype is unclear, particularly among patients who were in complete remission following induction, the authors noted. Sixty-nine children underwent HCT; 58 of whom did so in first complete remission. In the cohort of 31 patients with high leukemia burden at the end of induction (i.e., ≥5% leukemic cells) who underwent HCT, the five-year EFS was 83±15 percent, compared with 29±16 percent among non-transplanted children (p>0.05). However, the researchers added, the limited number of transplant recipients (and inherent selection bias of those who undergo transplantation) makes it difficult to evaluate HCT benefit among this patient group.

“With all the limitations, our observation points to the fact that patients with very poor response to induction treatment may be transplanted and rescued,” the authors concluded. “Major treatment-type modifications are thus to be considered only in children who do not achieve [first complete remission] by the end of induction.”

“The authors are to be congratulated for such an ambitious undertaking,” Patrick Brown, MD, told ASH Clinical News when asked for comment on the study. He added that “the creation of the infrastructure to support [future trials] is perhaps the greatest consequence of this important study.” Read more from Dr. Brown in “Perspectives”.

The study is limited by its retrospective design and that the findings need to be tested further in a prospective, multinational study. Some subgroups included small patient populations, which is another limitation of the study.

The corresponding authors report no financial conflicts.


Hrusak O, De Haas V, Stancikova J, et al. International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia. Blood. 2018 May 2. [Epub ahead of print]

“The major challenges to knowing how best to treat ALAL patients are the clinical and molecular heterogeneity within the ALAL subset and the lack of prospective clinical-trial data. The major challenges to researching ALAL are the rarity of this form of acute leukemia and the lack of a cooperative infrastructure to conduct clinical trials.

This study provides evidence that ALL-type induction therapy is associated with superior outcomes in ALAL, especially for ALAL cases that express CD19 (which accounts for about two-thirds of ALAL cases). The study also fails to demonstrate a clear benefit of HCT in ALAL.

The strength of the evidence is limited by two major factors. First, the study design is retrospective. Second, there were substantial differences in the distribution of known prognostic factors between the patients receiving ALL-type therapy and those receiving AML-type therapy (for example, cases with very high white blood cell counts were more likely to receive AML-type therapy). As the paper indicates, a subsequent prospective clinical trial that systematically tests the proposed treatment algorithms is in development. The creation of the infrastructure to support such a trial is perhaps the greatest consequence of this important study.”

Patrick Brown, MD
Director, Pediatric Leukemia Program
Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins University
Baltimore, MD