Inotuzumab ozogamicin is effective in relapsed/refractory extramedullary B acute lymphoblastic leukemia

A 66 years old woman, presenting increasing asthenia, revealed at peripheral blood count a severe anemia (Hb 7.3 g/dL), a reduced white blood cell (WBC) count (2400/μL) with severe neutropenia (neutrophils 600/μL), and a normal platelet count (PLT 168.000/μL). The diagnostic work-up showed a B-ALL, with normal karyotype, negative for BCR-ABL rearrangement and with immature B-cell origin (CD19+, CD22+, SMIg+, TdT+, CD20-). The CT-scan performed at diagnosis revealed a solid-lesion (7.0 cm width) at the right kidney’s inferior pole, that turned out to be a clear cell carcinoma (surgically removed later). The patient received 6 courses of chemotherapy according to BFM schedule, following local Institutional guidelines, including monthly intrathecal central nervous system (CNS) prophylaxis. After the first chemotherapy cycle, she reached a morphologic complete remission (CR) with MRD negativity, evaluated by analysis of clonal rearrangement of IgH gene study (according to Biomed EuroMRD Protocol [4]). Such a deep response was confirmed and maintained during all the six courses of chemotherapy.

After about 1 year and a half of sustained MRD negativity, blasts were documented at the peripheral blood smear. She performed a 18F-PET/CT (PET-CT), considering the recent history of renal cancer, that documented the presence of multiple lesions (Fig. 1a and d) [5], including a large pancreatic one. In order to define the following therapeutic approach, a differential diagnosis between renal cancer metastasis and EM-ALL localization was required. A pancreatic eco-endoscopic biopsy was performed, revealing a population of CD19+ and CD22+ lymphoid cells (Fig. 1g,h). Blast cells’ CD22 positivity suggested an approach with IO, which was obtained as compassionate use. IO was administered weekly in hospitalized regimen, for a total of three infusions (1,3 mg on day 1; 0,8 mg on day 8 and 15). Therapy was well tolerated, and no adverse events occurred. As expected, the bone marrow evaluation showed a morphologic CR, even with MRD positivity (10^-3). EM disease was still present, though, as detected by a PET-CT scan, which showed a slight reduction of the pancreatic lesion previously reported, with the onset of new hypermetabolic areas (Fig. 1b, e). Nevertheless, a second course of weekly IO was administered, for a total of four infusions (0.8 mg per dose). Surprisingly, the further PET-CT-scan documented a complete metabolic response (CMR) (Fig. 1c, f) associated with bone marrow MRD negativity. Currently, the patient is in good clinical conditions and still on IO (course 4), waiting for the identification of a matched-unrelated donor, not yet available, to proceed to allogenic bone marrow transplantation (allo-BMT).

A 67 years old man, suddenly presented muco-cutaneous bleedings associated with severe thrombocytopenia (PLT 13.000/μL), mild anemia (Hb 8.3 g/dL) and marked hyperleukocytosis (WBC 63.000/μL, 93% blast cells). The bone marrow examination showed a remarkable lymphoblast infiltration (TdT+, CD79a+, CD22+, CD19). Conventional cytogenetic analysis revealed t(9;22). Therefore, the diagnosis of BCR-ABL1 (p190)-positive B-ALL was made. The patient received a 7-day steroid pre-phase followed by ponatinib (Iclusig) at the initial dose of 15 mg daily, rapidly increased to standard dosage, 45 mg/daily, associated with monthly medicated lumbar punctures (methotrexate, cytarabine and dexamethasone), according to the GIMEMA LAL1811 clinical trial (NCT01641107). He obtained a morphological CR after 10 days of ponatinib, while MRD evaluated by real-time PCR never reached values below 0.003 copies (assessed by BCR-ABL/ABL ratio). Therapy was well tolerated and continued for 18 months, until the patient presented a painless skin lesion on the forehead, that turned out to be a CD19+ CD22+ EM-ALL localization. Bone marrow was still negative for leukemic infiltration. After local radiotherapy (4000 cGy) the skin lesion completely resolved, but the PET-CT scan control, performed just 2 months later, revealed multiple new hypermetabolic thoracic and abdominal lesions. Therefore, the patient received two courses of chemotherapy, according to BFM schedule. Therapy was complicated by an episode of gastrointestinal bleeding (melena with severe anemia) caused by duodenal and gastric disease localizations, documented bioptically (Fig. 2d-f). The PET-CT scan after the chemotherapy courses (Fig. 2a) showed a remarkable disease progression (PD). Immunohistochemistry of duodenal biopsy had showed CD22 positivity, suggesting a possible efficacy of IO therapy, obtained as compassionate use. He underwent two IO courses according to standard schedule without the occurrence of any adverse event. The following bone marrow analysis documented a persistent morphological and cytogenetic CR, but still MRD positivity (BCR-ABL/ABL 0.03 copies). The PET-CT scan showed the progressive decrease of all previously described lesions (Fig. 2b, c), reaching a partial metabolic response (PMR), because of the persistence of a pathologic hypermethabolic areola. The patient proceeded to allo-BMT 1 month later. No GVHD occurred, and no VOD/SOS (Veno-occlusive disease/Sinusoidal occlusive syndrome) was observed. To sum up, the patient had several EM “outbreak” relapses, while the bone marrow morphologic complete remission with MRD positivity was maintained. None of the therapies he underwent (TKI, local radiotherapy, chemotherapy, IO) lead to MRD negativity. However, notably, only IO induced an important reduction of extramedullary disease localizations.