Clinical history
We identified 4 families, each with two siblings, who developed
hematological neoplasms. Of these 8 patients, 7 (87.5%) developed acute
myeloid leukemias (AML; see Table 1 for clinical details). Patient ID4
of Family2 developed a Philadelphia-positive chronic myeloid leukemia
(Ph+ CML). The detailed clinical history of each family is described
below.
Family1. Sister ID1 was diagnosed with hyperleukocytotic
AML with normal karyotype (NK) at 17 years of age. She received a
regimen (LAME 89 pilot study) including an intensive induction phase
(mitoxantrone plus cytarabine) and obtained complete remission. She then
received two consolidation courses: the first containing
timed-sequential high-dose cytarabine, asparaginase and amsacrine; the
second consisting of mercaptopurine plus cytarabine for 18 months. She
is now 40 years old and still in complete remission (CR).
Sister ID2 also received a diagnosis of AML with NK when she was 32
years old. She obtained CR following induction therapy with the 3+7
schedule (cytarabine 100 mg/mq G1, daunorubicin 60 mg/mq G1-3-5). She
then received 4 consolidation therapy courses with high doses of
cytarabine. After 2 years from end of treatment, she is persistently in
CR. Both sisters are currently under close clinical monitoring.
Family2. Brother ID3 developed AML with karyotype
46,XY,del(16)(q22qter)[7]/46,XY[13] at age 62. He received ICE
(idarubicine, cytarabine and etoposide) as induction chemotherapy and
achieved CR. He then received a consolidation cycle with high dose
cytarabine, and peripheral-blood stem cells (PBSC) were harvested during
recovery. He underwent autologous PBSC transplantation as final
consolidation therapy, but relapsed a year later. Molecular evaluation
identified a known JAK2 V617F mutation (Table 1) and additional
mutations in the ASXL1 (p.G1185Cfs*4, Varian Allele Frequency
(VAF)=3.09%) and RUNX1 (p.L405Cfs*, VAF=4.71%) genes (not
shown). The patient, therefore, received reinduction chemotherapy with
FLAI (fludarabine, idarubicine and cytarabine) and a consolidation cycle
with high-dose cytarabine, achieving CR. Four months later he underwent
myeloablative allogeneic haploidentical stem-cell transplantation from a
family donor (conditioning: fludarabine, cyclophosphamide, total body
irradiation and cyclophosphamide +3 and +4 post reinfusion), complicated
by occurrence of veno-occlusive disease, which was treated and resolved
with defibrotide. Approximately 1 year and 9 months after
transplantation, he is in CR in fair general condition.
Brother ID4 was diagnosed with Ph+ CML, Sokal score low risk, in absence
of additional cytogenetic alterations at age 53. He started therapy with
imatinib but immediately developed intolerance and, therefore, changed
to dasatinib (tyrosine kinase inhibitor - TKI- 2ndgeneration), achieving complete molecular response. Three years after
starting therapy, he developed laterocervical lymphadenopathy and
persistent fever; he was deemed intolerant to dasatinib, which was
discontinued. He then started therapy with ponatinib
(3rd generation TKI), with persistence of molecular
remission to date.
Family3. Brother ID5 was diagnosed with AML
characterized by myelodysplastic changes, NK and mutations inTET2, ASXL1 and U2AF1 genes (Table 1) at age 74. He was
treated with ICE to which the patient was refractory. Therefore,
reinduction chemotherapy according to FLAI plus venetoclax was
performed, resulting in CR. Four months later, he underwent
myeloablative haploidentical allogeneic transplantation (conditioning as
for brother ID3), maintaining CR and achieving complete full chimera.
Seven months after transplantation, he showed reduction in chimerism
with worsening of blood counts and progressive need for transfusion
support. Subsequent BM evaluation showed no increase in blasts, a
progressive increase in VAF of TET2 , ASXL1 andU2AF1 mutations and acquisition of a TP53 mutation (Figure
1A). These clinical and molecular parameters were considered indicative
of disease relapse. The patient was then treated with salvage therapy
(azacitidine + venetoclax) followed by worsening of his general
condition and progressive leukocytosis; BM evaluation showed
refractoriness of the disease with transformation into megakaryoblastic
AML. The patient died of disease progression approximately one year
after transplantation.
Brother ID6 was diagnosed with AML bearing trisomy of chromosome 8 at
age 61. He received induction chemotherapy with ICE achieving CR. He
received further cycles of IC (idarubicin and cytarabine) as
consolidation and cycle A8 (cytarabine) followed by reinfusion of
autologous PBSCs. When in chronic remission, he underwent allogeneic
myeloablative transplantation from a volunteer donor (conditioning:
busulfan, fludarabine, ATG). Post-transplantation recovery, he was
undermined by a state of immunosuppression, showing Cytomegalovirus
(CMV) reactivation resistant to antiviral treatments, which resulted in
graft failure (requiring a boost of PBSCs from the same donor),
Gram-positive encephalitis and finally Geotrichum sepsis, which led to
patient’s death approximately 10 years after transplantation.
Family4. Sister ID7 received diagnosis of AML with
myelodysplastic changes and NK when she was 58 years old. NGS mutational
analysis of blasts for clinical assessment showed presence of mutations
in SF3B1 , TET2 and ETV6 (Table 1). She received
induction therapy with 3+7 scheme plus gentuzumab ozogamicin (as part of
the GIMEMA 1819 protocol). However, she did not obtain remission and
underwent a cycle of reinduction according to FLAI plus venetoclax,
obtaining only partial response with persistence of the SF3B1 ,TET2 and ETV6 mutations (Figure 1B). Within one month, the
disease relapsed and she underwent a further cycle of therapy with
azacitidine plus venetoclax, obtaining complete response. She then
underwent haploidentical allogeneic transplantation (conditioning with
treosulfan + fludarabine). Nine days after, she had an acute episode of
cerebral hemorrhage, which caused her death.
Brother ID8 was diagnosed at age 73 with AML displaying myelodysplastic
changes, NK and presence of the hotspot IDH2 mutation (Table 1).
He achieved CR after the first course of azacitidine plus venetoclax
therapy. To date, he underwent 8 chemotherapeutic cycles, maintaining
CR.