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.