[Antibody-Drug Conjugate for Treating Leukemia and Lymphoma-The Present Status, Problems, and Future Development].

Antibody-drug conjugate(ADC)contain monoclonal antibodies that target-specific tumor antigens, cytotoxic payloads, and linkers. ADCs use antibodies to selectively act on tumors, making them more effective and less toxic. In Japan, 4 drugs are approved as ADCs for leukemia and lymphoma: gemtuzumab ozogamicin(GO)consists of an anti-CD33 monoclonal antibody bound to calicheamicin via a linker, approved for relapsed/refractory acute myeloid leukemia. Brentuximab vedotin (BV)has anti-CD30 antibodies bound to MMAE via a linker and is approved for CD30-positive Hodgkin's lymphoma, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma. BV, in combination with multi-agent chemotherapy, resulted in significantly prolonged progression-free survival(PFS)in classical Hodgkin's lymphoma and peripheral T-cell lymphoma compared to the control group. Inotuzumab ozogamicin(IO)has an anti-CD22 antibody bound to calicheamicin via a linker, approved for relapsed/refractory CD22-positive B-cell acute lymphoblastic leukemia. In relapsed/refractory B-cell acute lymphoblastic leukemia, IO showed a higher complete remission rate than the control group. Polatuzumab vedotin(PV)has an anti-CD79b monoclonal antibody bounds to MMAE via a linker, approved for diffuse large B-cell lymphoma(DLBCL). In DLBCL patients with an international prognostic index score(IPI score)of 2 or higher, the combination of PV plus rituximab, cyclophosphamide, doxorubicin, and prednisone(PV+R-CHP)extended PFS at 2 years compared with R-CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), which has long been the standard of care. As shown, ADCs exhibit high therapeutic efficacy in leukemia and lymphoma treatment, but many aspects of their resistance mechanisms remain unclear and require further research.

Combining inotuzumab ozogamicin with PARP inhibitors olaparib and talazoparib exerts synergistic cytotoxicity in acute lymphoblastic leukemia by inhibiting DNA strand break repair.

Inotuzumab ozogamicin (IO), a novel therapeutic drug for relapsed or refractory acute lymphoblastic leukemia (RR)­(ALL), is a humanized anti­cluster of differentiation (CD) 22 monoclonal antibody conjugated with calicheamicin that causes DNA single­ and double­strand breaks. Although the efficacy of IO is significantly improved compared with that of conventional chemotherapies, the prognosis for RR­ALL remains poor, highlighting the need for more effective treatment strategies. The present study examined the role of DNA damage repair inhibition using the poly (ADP­ribose) polymerase (PARP) inhibitors olaparib or talazoparib on the enhancement of the antitumor effects of IO on B­ALL cells in vitro. The Reh, Philadelphia (Ph)­B­ALL and the SUP­B15 Ph+ B­ALL cell lines were used for experiments. Both cell lines were ~90% CD22+. The half­maximal inhibitory concentration (IC50) values of IO were 5.3 and 49.7 ng/ml for Reh and SUP­B15 cells, respectively. The IC50 values of IO combined with minimally toxic concentrations of olaparib or talazoparib were 0.8 and 2.9 ng/ml for Reh cells, respectively, and 36.1 and 39.6 ng/ml for SUP­B15 cells, respectively. The combination index of IO with olaparib and talazoparib were 0.19 and 0.56 for Reh cells and 0.76 and 0.89 for SUP­B15 cells, demonstrating synergistic effects in all combinations. Moreover, the addition of minimally toxic concentrations of PARP inhibitors augmented IO­induced apoptosis. The alkaline comet assay, which quantitates the amount of DNA strand breaks, was used to investigate the degree to which DNA damage observed 1 h after IO administration was repaired 6 h later, reflecting successful repair of DNA strand breaks. However, DNA strand breaks persisted 6 h after IO administration combined with olaparib or talazoparib, suggesting inhibition of the repair processes by PARP inhibitors. Adding olaparib or talazoparib thus synergized the antitumor effects of IO by inhibiting DNA strand break repair via the inhibition of PARP.

[Lineage switch from T-lymphoblastic leukemia to myeloid leukemia at relapse].

A 38-year-old woman was referred to our hospital because of fever, general malaise, and abnormal blood count. The white blood cell count was 19,500/µl, with 72% lymphoblast. Bone marrow examination showed increased cellularity with 94% lymphoblast. Flow cytometry revealed the following T-cell lineages: cyCD3 (+), CD5 (+), CD7 (+), and CD34 (+). Chromosome analysis revealed hypodiploidy. The patient was diagnosed with early T-cell precursor lymphoblastic leukemia (ETP-ALL). After two cycles of induction chemotherapy, she achieved complete remission, but the disease relapsed after one cycle of consolidation therapy. At the time of relapse, leukemic cells were myeloperoxidase positive and showed a loss of T-cell surface antigen, suggesting that a lineage switch occurred. The patient did not respond to the second induction therapy. She subsequently received 3+7 (idarubicin+cytarabine) for acute myeloid leukemia (AML), but she deceased due to refractory leukemia. At the time of relapse, genome sequencing was performed and mutations of NRAS, TP53, and MLLT-PICALM fusion genes were revealed. Here, we report a case of ETP-ALL who relapsed with a lineage switch to AML in concordance with refractory disease.

The clinical significance of CD49e and CD56 for multiple myeloma in the novel agents era.

Multiple myeloma (MM) is a hematological malignancy characterized by the proliferation of abnormal plasma cells in bone marrow. Flow cytometry distinguishes between normal and abnormal plasma cells by evaluating cluster of differentiation (CD) 56 and CD19 expression patterns. Moreover, immunophenotyping of mature plasma cell 1 (MPC-1) and very late antigen-5 (CD49e) identifies the maturity of MM as mature (MPC-1+, CD49e+), intermediate (MPC-1+, CD49e-), or immature (MPC-1-, CD49e-). We retrospectively examined the effects of surface marker expression and maturity subtype on overall survival (OS) and time to next treatment (TNT) among 55 patients (25 males, 30 females) with symptomatic MM. All patients were treated with regimens containing bortezomib (BOR) (n = 39) or lenalidomide (LEN) (n = 16) as the initial treatment. Median age at diagnosis was 72 years (range: 36-88). The lack of CD56, an aberrant marker, was associated with significantly worse prognosis compared with CD56+ MM (median OS: 24 vs. 60 months, respectively; p = 0.0050). In CD49e+ MM, defined as mature type, no significant difference was seen in TNT of the initial treatment, regardless of whether it was a BOR-based regimen or LEN + dexamethasone (Ld) therapy. On the other hand, in CD49e- MM, defined as immature/intermediate type, TNT of Ld therapy was significantly longer than that of BOR-based regimens (median TNT: undefined vs. 12 months, respectively; p = 0.0043). These results suggest that Ld therapy is more effective than BOR-based therapy for CD49e- MM and thus may aid regimen-related decisions in the novel agents era.

Clinical Significance of Inotuzumab Ozogamicin in Non-transplant Patients with Relapsed Acute Lymphoblastic Leukemia: A Report of Four Cases.

Relapsed acute lymphoblastic leukemia (ALL) has a poor prognosis. Inotuzumab Ozogamicin (InO) is a novel therapeutic drug for the treatment of relapsed ALL. InO has received attention as a bridging therapy before transplantation due to its high complete remission (CR) rate. However, the significance of InO in non-transplant patients remains unclear. We retrospectively evaluated four non-transplant patients treated with InO. All cases achieved CR after receiving at least two cycles of InO. Three of the four cases survived for more than 11 months without relapse. Moreover, all patients received InO as outpatients, because the adverse events were well-controlled. InO therefore appears to be a beneficial treatment even for non-transplant patients.

A Comparison of PMDA and EMA Consultations for Regulatory and Scientific Matters in Drugs and Regenerative Medicine Products.

The Pharmaceuticals and Medical Devices Agency (PMDA) and the European Medicines Agency (EMA) have provided a wide range of regulatory and scientific consultation menus to cover any development stage of drugs and regenerative medicine products, respectively. The current study compares Consultations by PMDA and Scientific Advice by EMA in terms of consultation types, consultation performances, and specific consultation procedures with timelines. Each agency sets intensive but highly professional procedures and timelines in order to provide sufficient advice in a timely manner. Both agencies complete the consultation process for approximately 3 months while an application is reviewed by experts and close communication with the applicant is provided. Although PMDA and EMA have some differences of approaches to provide well-considered scientific opinions as quickly as possible, both agencies have made efforts to support the development of better products for patients. Sharing technical insights through consultation experiences will contribute to earlier access of patents to new products in both Japan and the EU.