B-Cell Precursor Acute Lymphoblastic Leukemia/ Lymphoma with MYC and BCL-2 Rearrangements, a Case Report of an Unclassified “New” Entity

    

    

    Figure 2: A-B: PET-CT before first line chemotherapy showing diffuse extranodal disease localization, including the right testicle, the stomach and two cutaneous lesions, C-D Partial Remission showed in PET-TC after 2 cycles of courses B of R-HyperCVAD.
    

Due to the many extra-nodal sites involved, a diagnostic lumbar puncture was first performed showing meningeal disease [107 cells, 8000 events in Flow Cytometry (FC)] and the patient received a weekly intrathecal chemotherapy with methotrexate, cytarabine and prednisone, resulting in a progressive reduction of events in FC, without never reaching liquor sterilization. Intrathecal treatment was later interrupted due to chronic headache and liquor hypotension syndrome and never performed again. Due to the severe hyponatremia, the patient was studied for a suspected panhypopituitarism, which was confirmed on blood tests and explained by meningeal disease, in absence of disease localization in MR. Replacement treatment with levothyroxine, oral corticosteroids and desmopressin was administered.

After the first two cycles of chemotherapy the patient obtained a PR and the unrelated donor research was started (having a brother suffered from a testicular cancer) with the intent of giving an early treatment with allogeneic stem cells transplantation. The patient was discharged from the hospital in good clinical conditions. The next day, he came to our emergency room for unexplained episodes of seizures, confusion associated with urinary incontinence. The head CT and MR showed a hygroma with early signs of tonsillar herniation caused by liquor hypotension syndrome and he was treated with mannitol, dexamethasone and diuretics. In August, after completing first course A of R-HyperCVAD (CTX 300 mg/12 hours from day 1 to 3, doxorubicin 50 mg on day 4 and dexamethasone 40 mg from day 1 to 4 and from day 11 to 14), avoiding vincristine due toits neurotoxicity, the patient was again discharged in good clinical conditions.

After a couple of weeks, the patient was hospitalized again for FUO, headache and nausea. Antibiotics were started, with no microbiological finding. The patient underwent a new disease evaluation in PET-TC that showed a Progressive Disease (PD) in the same localizations that were known at diagnosis. New cutaneous lesions appeared that were consistent with BCP-ALL, while the hygroma was stable in MR and bone marrow aspirate was again negative for infiltrate. After one more week, the patient presented right eyelid ptosis (CT head negative) that was treated with no benefit with High dose dexamethasone and never resolved.

The patient underwent second line treatment with the two cycles of HAM regimen (citarabine 3g/mq every 12h from day 1 to day 4, mitoxantrone 10 mg/mq from day 3 to day 5). During this period, he suffered from septic shock caused by Klebsiella Pneumoniae Carbapenemase-producing (KPC) and began Isavuconazole due to positivity of Galactomannan (GMN) antigen in samples of bronchoalveolar lavage and fungus ball images at CT scan.

On day 14 of the second cycle of HAM, the patient presented increasingly elevated lactate LDH levels, a growth of the cutaneous lesions and was evaluated with a Total body CT scan that showed PD and bilateral thrombosis of both pulmonary arteries, treated with anticoagulant therapy.

In October after the clinical progression of disease, the patientbegan third line therapy with “Teddi” [6] regimen (temozolomide 200 mg os from day 1 to day 5, etoposide 100 mg/ mq from day 1 to day 3, dexamethasone 40 mg from day 1 to day 4, Caelyx 40 mg/mq on day 1 and daily Ibrutinib 560 mg die os). On day 15, the patient suffered from severe hyponatremia, LDH levels were at highest and he suffered from episodes of unconsciousness. On day 16, Ibrutinib was suspended due to asevere hemorrhagic cystitis caused by KPC. On day 24, the patient suffered from one more epilepsy attack and, sequentially, a cardio-respiratory arrest. Despite reanimation, the patient died after three more days.

Discussion

The presence of both C-MYC and BCL-2 rearrangements in B-Cell lymphomas defines a DHI: such finding is associated with a higher CNS involvement, a more advanced stage, an inferior response to chemotherapy and a poorer prognosis [7]. DLBCLs harbor simultaneous MYC and BCL-2/6 rearrangements in at least 5-10% of all cases [8]. A single rearrangement of MYC occurs in 5-10% of BCPALL, is associated with hypodiploidy and mutated TP53 and brings a poorer outcome [9,10]. BCL-2 is mostly rearranged in proximity of IgH locus, while MYC is rearranged in both IgH – non IG locus, with no difference in survival. DHI with BCL-6 is less common [11]. In a recent, Miyaoka et al., reviewed 25 patients with this particular finding in Follicular lymphomas, concluding that there were no prognostic differences instead of HGBLs [12].

De novo DH-BCP-ALLs affect patients of all ages, with no significant difference in gender; usually present themselves with high WBC counts, elevated LDH levels and systemic symptoms. Most cases show a diffuse bone marrow infiltration, CNS involvement (one/third showed meningeal infiltration) and extramedullary disease, which is mostly gastrointestinal, in the salivary glands and paraosseal.

Immuno-phenotypic analysis shows immature B-Cell onset (CD10+, CD19+, TdT+, IgM-), high expression of MYC e BCL- 2 and a complex karyotype. In the previously cited review, 60% of the patients, which were enrolled in different protocols (mainly ALL-based), achieved a nearly hematologic remission. All patients received an intrathecal prophylaxis with methotrexate and cytarabine; however, most of them relapsed within 12 months with a median OS after relapse of 2.5 months. In a 2015 review, Wei Liu et al presented three pediatric cases of DH-BCP-ALLs that shared the same clinical and pathological characteristic previously described for adult patients [13].

Conclusion

Our patient shared clinical features with those known in literature, such as the CNS involvement, as previously reported in DH-BCPALLs reviews, but differed in immune-phenotypical analysis (IgM positive, Tdt + in 10% of the cells), in cytogenetic (normal karyotype) and in the absence of disease infiltration in bone marrow.

This case report confirms that DHI and THI do not fall into a single WHO category, as MYC and BCL-2 rearrangements are observed in DLBCL, in FL and also in BCP-ALL.

We can infer that, when DH-BCP-ALLs diagnosis is made, intensive treatment regimens are required to achieve an early complete response, however there is no evidence of which regimen should be preferred.

Early relapse is the main factor correlating to a poor prognosis in all cases observed so a consolidation therapy, such as Allogenic stem cell transplantation, could be considered.

Screening search of MYC, BCL-2 and BCL-6 may be helpful to recognize de novo DH-BCP-ALLs and provide a fine therapeutic approach to such disease. Flow cytometry plays a crucial role, analysis of CD3, CD10, CD13, CD33, CD19, CD20, surface kappa/lambda light chain, cytoplasmic TdT and cytoplasmic CD 22 is recommended [10].

References

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