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The spectrum of CBL-mutated JMML
median survival: 7.9 years) for patients who did not under- go HSCT (Figure 2B, C). Of note, all three deaths in the non-transplanted cohort were due to other organ failure associated with CBL-syndrome unrelated to JMML. There was no difference in overall survival between the patients with germline CBL mutations and those with somatic CBL mutations (Online Supplementary Figure S1).
We observed that all five patients with somatic CBL mutations were refractory to moderately-intense myeloid- based chemotherapy (i.e., 2 g/m2/day cytarabine alone or in combination with 30 mg/m2/day fludarabine).1 Three of
A
B
C
Figure 2. Kaplan-Meier survival curves for CBL-juvenile myelomonocytic leukemia. (A) Overall survival of the whole cohort (n=33). (B) Overall survival of patients who underwent hematopoietic stem cell transplantation (n=15). (C) Overall survival of patients who did not undergo hematopoietic stem cell trans- plantation (n=17). One patient who was lost to follow-up was not considered in analyses for (B) or (C). HSCT: hematopoietic stem cell transplantation; w/o: with- out.
these five patients received an allogeneic HSCT, and two are alive and disease-free at the time of last follow-up. One relapsed with frank acute myeloid leukemia following allo- geneic HSCT for JMML and died of infectious complica- tions (Vignette 1).
The clinical courses of the 28 patients with germline CBL mutations were heterogeneous. Three patients experienced spontaneous resolution of JMML without any treatment. Two patients underwent splenectomy as their only treat- ment but both died several years later of CBL-syndrome- associated organ failure (Vignette 2). Twelve patients received allogeneic HSCT following different pretransplant therapies. Nine of the transplanted patients went into remission after the transplant (2 after graft failure [Vignette 5 in the Online Supplementary Material and a separate case previously described by Oshrine.22]). Among the remaining three patients who were transplanted, two died of relapsed JMML and one died of transplant-related complications.
Of the 11 patients who were not transplanted and did not experience spontaneous resolution, nine have persistent disease without having been transplanted to date. The median follow-up of these patients is 3.5 years and their treatments included low-dose chemotherapy (Vignette 3), moderately-intense acute myeloid leukemia-directed chemotherapy, azacitidine, and/or targeted agents. Several patients received no therapy, while others were refractory to multiple lines of therapy. One patient with multiple con- genital abnormalities died from complications of multi- organ failure in infancy. One patient was lost to follow up. An overview of all disease courses is shown in Figure 3.
Methylation-based clustering of patients’ samples
In order to investigate whether DNA methylation pro- files are capable of distinguishing patients who will experi- ence spontaneous resolution from those with more aggres- sive disease, we assessed the methylation of approximately 3,000 CpG loci using peripheral blood of each patient at diagnosis. Patients were designated as having low, interme- diate or high methylation based on minimum distance to the centroid of the international consensus definition
Table 2. Comparison of clinical characteristics of patients with germline or somatic-only CBL mutations.
Median age at diagnosis, years Range
Gender Male
Female
Median WBC at diagnosis, x109/L Range
Median absolute monocyte count at diagnosis, x109/L
Range
Median platelet count at diagnosis, x109/L
Range
Median hemoglobin at diagnosis, dg/L Range
Elevated hemoglobin F for age Abnormal cytogenetics Splenomegaly
P-value 1.0 0.79
Germline CBL (n=28)
1.1 0.1-25.3
12 16
31.7 6.9-196.0
5.5
0.8-31.1 62
10-204
9.7 6.2-11.8
18% 4% 96%
Somatic CBL (n=5)
0.6-3.5
2 0.85 3
43.0 0.58 24.1-88.0
6.7 0.96
4.4-12.0
102 0.56
42-167
10.4 0.34 8.9-11.7
20% 0.91 0% N/A 100% N/A
WBC: white blood cell count; N/A: not applicable.
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