In our cohort of 150 cases of acute leukemia, we detected 9 cases with rare non-recurrent chromosomal abnormalities of which 4 cases were ALL, 4 cases were AML and one case was biphenotypic AL (B/Myeloid). Two cases with hypodiploidy (2n-), t (5;14) (q31;q32) and t (3;11;19)(q21;q23;q13.1) were detected in ALL. The AML patients were found to harbor t (7;14) (q22;q32), t (11;17)(p15;q21), t (11;20)(p15;q11), t (12;17)(q15;q23) and t (11;20)(p15;q11). Both t (1; 15) (q10; q10) and t (17; 19) (q21; p13.3) were detected in the case with biphenotypic AL. The demographic, hematological and cytogenetic data of these 9 cases are summarized in Table 1& Table 2 and Figs. 1, 2, 3, 4, 5, 6, 7. Complete remission (CR) status was achieved in 3 patients. The remaining 6 patients never attained CR, relapsed or demised.
Acute lymphoblastic leukemia cases
Case 1
This 4 year old B-ALL patient was negative for ALL panel specific abnormalities with a normal female karyotype (46, XX) (Fig. 1). Hypodiploidy (2n-) with loss of -1, -8, -9, -11,-12,-19 and -22 was detected in 80% of the studied cells by FISH (Figs. 2, 3, 4, 5). Thereafter, cryptic abnormalities were identified (not detected by the initial karyotyping (Fig. 1). The interesting finding in this case was that the diagnostic karyotype was normal but the FISH showed 2n-. This indicated that FISH revealed the cryptic cytogenetic abnormality which was not detected by GTG-banding karyotype.
The patient was classified on very high risk ALL chemotherapy protocol (COG AALL0031). During induction chemotherapy the patient developed a gluteal ulcer and recurrent infections with positive blood cultures which we treated with antibiotic therapy. The post induction BM aspirate revealed 6% of blasts with the immunophenotype presentation compatible with partial remission. The patient received 2 weeks of extended induction chemotherapy. The BM aspirate on day 43 showed morphological remission. Cytogenetics was negative for all detected tumoral clones except for the 2n- which persisted. The patient then received intensified consolidation phase chemotherapy and is currently awaiting BM transplant.
Case 2
This 7 year old B-ALL patient harbored the classical ETV6 /RUNX1 rearrangement in the majority of analyzed cells. However, a clonal evolution with loss of der (12)- and the MYC gene rearrangement was detected in 20% of cells. The karyotype showed 44, XX; del (4); del (8) and t (12; 17) (p13; q21) (Fig. 6).
The patient was classified on standard risk chemotherapy protocol (COG AALL0331). The post induction BMA showed CR. The clinical decision was to continue the chemotherapy protocol in consideration of the mild 2n- . Hypodiploidy (2n) - < 45 chromosomes is uncommon. Despite improved treatment outcome of childhood ALL, patients with hypodiploid ALL have a dismal prognosis [6,7,8].
Case 3
This 11 year old patient presented with vomiting, diarrhea and generalized weakness for 3 weeks. The full blood count detected leukocytosis with marked eosinophilia. The BM was hypercellular with eosinophilia (50%) (Fig. 7) and blasts (40%) (Fig. 8) with B-ALL immunophenotype. The cytogenetic and molecular analysis detected t (5; 14) (q31; q32) by FISH. RT-PCR was negative for PDGFRA, PDGFRB, and FGFR1 gene abnormalities. We diagnosed the patient with concurrent B-ALL and hypereosinophilia.
The patient was classified on steroid therapy and on high-risk chemotherapy at the time of diagnosis. Post induction chemotherapy analysis showed morphological(< 3% blasts/ no eosinophil’s in the BM) and molecular (negative IGH gene rearrangements) remission. The patient is currently in CR status on high dose methotrexate therapy for maintenance.
The t (5, 14) in association with eosinophilia has not been frequently reported in the literature. A single case report of a 6 year old boy presenting with hypereosinophilia and associated Loeffler endocarditis has been previously recorded [8]. Three months following his initial hypereosinophilia this patient developed cutaneous B-lymphoblastic lymphoma. Re-analysis of apparently uninvolved BM revealed a single, previously unidentified.
t (5; 14) (q31; q32) positive cell. IL3 / IGH @ fusion were demonstrated in cutaneous lymphoma cells. Our patient also showed the IL3/IGH gene translocation strengthening the association of IL3 hypersecretion and hypereosinophilia [8].
Case 4
This 18 year old T-ALL patient presented with the typical T cell immunophenotype on 40% of blasts (CD45 dim, CD4, CD8, CD7, CD5, CD2, CD38, CD34, cCD3). The karyotype was 46,XY; t (3;11;19)(q21;q23;q13.1) (Fig. 9). FISH was positive for MLL gene rearrangement (Fig. 10). An extra copy of the MYC gene was detected in 40% of the studied cells (Fig. 11).
The patient was classified on DANA FARBER protocol but did not respond. FLAG-IDA salvage chemotherapy high dose was started. The patient, however, never attained CR and subsequently demised. To the best of our knowledge, this is the first case reported in the literature harboring this complex translocation.
Acute myeloid leukemia cases
Case 5
This 3 year old AML M4 patient showed t (11; 17) (p15; q21), tetrasomy (4n) of chromosome 8 and two extra copies of MYC in 85 and 70% of the studied cells (Fig. 12).
The patient was classified on the first cycle of MRC AML12 protocol. On day 5 post chemotherapy the patient developed neutropenia and persistent high grade fever. The patient was given Vancomycin and Amikacin following blood cultures and Meropenem for a urinary tract infection. Prophylactic fluconazole was started. On the final chemotherapy cycle the patient developed bloody diarrhea and abdominal distention. The abdominal ultrasound and CT Abdomen revealed a severe typhilitis. Despite intensive care support, the patient demised following cardiopulmonary arrest and multi-organ failure one month after admission.
Only 3 cases of pediatric AML with the t (11; 17) (p15; q21) have been previously reported: two AML M4 cases (aged 3 and 4 years) one AML M0 case [9,10,11]. Another MDS case with isolated t (11; 17) (p15; q21) after neuroblastoma chemotherapy has been reported in an 8 years old girl [12]. In adults, the translocation has been reported in one case [12].
Case 6
This 14 year old patient was diagnosed with Hodgkin’s Lymphoma (HL) stage 3-A and was in remission for 5 years. The patient was treated with ABVD and CHIVPP. He arrived at the Emergency Unit with the clinical symptoms of melena stools, fever, fatigue, lymphadenopathy and hepatosplenomegaly. The BM and immunophenotype was compatible with AML MO. A lymph node biopsy showed a myeloid sarcoma.
Chromosomal analysis detected the karyotype 46, XY, t (7; 14) (q22; q32). FISH was negative for AML panel specific abnormalities. After initiation of induction chemotherapy the patient developed persistent neutropenia with klebsiella infection and did not attain remission status. He was classified on high risk MAC/G protocol. He continued to have chemotherapy related side effects such as afebrile neutropenia, severe mucositis and multiple resistant bacterial and fungal infections. The patient failed to recover or attain remission status and subsequently demised. This is rare presentation of AML MO with t (7, 14) in a patient with previous HL.
Secondary leukemia’s as in this patient commonly manifest with abnormalities of chromosome 7 and 5, however, the t (7; 14) (q22; q32) commonly occurs in T-ALL and rarely in AML [13, 14].
Case 7
This 18 year old patient was diagnosed as AML (M2) both morphologically and immunophenotypically. Aberrant expression of CD7 occurred on a cellular subpopulation. Cytogenetic analysis showed 46, XY; t (11, 20) (p15; q11) and add (21) (p11) (Fig. 13). The patient started the first cycle of AML induction chemotherapy (3 + 7) protocol and achieved CR.
This t (11; 20) (p15; q11) is a rare chromosomal translocation which has a poor prognosis [15, 16]. Our case responded well to 3 + 7 protocol (3 doses of Daunorubicin+ 7 days of cytosine arabinoside) and attained CR. The patient then had allogeneic stem cell transplant and later developed steroid refractory graft versus host disease which was treated with ATGA.
Case 8
This 5 year old patient presented with anemia and thrombocytopenia. He received IVIG infusion as ITP (immune thrombocytopenic purpura) was suspected, but no improvement occurred. A BM aspirate immunophenotype was compatible with AML (FAB; M7). The cytogenetic analysis revealed a complex karyotype t (12;17)(q15;q23) and 48,XY,+ 2,del (7)(p15), inv. (8)(q22q24), t (12;17) (q15;q23) and trisomy 19. FISH reported PML/RARA; RUNX1 / RUNX1T1; (5’CBFB, (3’CBFB,5’CBFB con 3’CBFB) / (5’MLL (3’MLL,5’MLL con 3’MLL). In addition, a tumoral clone with extra chromosome (2+) and (19+), del (7p), inv.(8) and t (12; 17) (Fig. 14) was detected.
The patient was treated on MRC AML12 Protocol but did not attain remission and subsequently demised. This very rare t (12; 17) has been reported in three adults and one child with secondary AML [17, 18]. Interestingly, the four published cases have been female and have additional aberrations. Our patient is male and the translocation is also part of a complex karyotype.
Case 9
This 4 year old patient was diagnosed as biphenotypic acute leukemia (B /Myeloid). Morphology of two morphologically diverse populations of cells immunophenotypically expressed myeloid markers (CD13, CD33 and MPO) and B cell markers (CD10, CD19, CD79a, and TdT).
The cytogenetic analysis revealed the presence of a cell line with der t (1;15)) (1q10; 15q10) and t (17q21; 19p13.3). The FISH panel was negative for all gene abnormalities.
We diagnosed a biphenotypic (B /Myeloid) leukemia with the rare t (1; 15) present in the AML clone and t (17; 19) present in the B-ALL clone. The patient was classified on MRC AML12 protocol. The post induction BM showed persistent disease (60% blasts). A second ADE was given and the BM showed a regenerating marrow with 5% clonal blasts. A third cycle of the protocol MACE and fourth cycle CLASP were given and samples were taken for matched unrelated donor transplant. During the fourth chemotherapy cycle, the patient developed septic shock and the protocol was changed to a fifth chemotherapy cycle MidAC. A month after completing this cycle, the patient presented with fever, bone aches and neutropenia with circulating blasts. The BM aspirate showed relapse with 60% blasts. The patient was classified on FLAG-IDA (the sixth chemotherapy protocol). However, the patient remained refractory. In addition, the patient developed febrile neutropenia and was started on antibiotics, antifungal therapy and a 7th course of chemotherapy. A matched unrelated donor transplant was planned by the treating physicians in view of the persistent refractory disease.