First reported case of secondary mixed phenotype acute leukemia after multiple myeloma.

In recent years the outcome of patients with multiple myeloma (MM) has significantly improved, due to new drugs. However, some agents, i.e. the alkylating drug melphalan, can be associated with an increased incidence of secondary malignancies. Myelodysplastic syndromes and acute myeloid leukemia are reported in the literature, and rarely acute lymphoblastic leukemia. Here we describe a unique case of a 56-years old female patient affected by MM since 2015 in complete remission after autologous stem cell transplant and in lenalidomide maintenance, who developed 2 years later mixed phenotype acute leukemia (MPAL). The patient, refractory to both lymphoblastic and myeloid acute leukemia regimens, achieved complete remission with bi-specific anti-CD19/anti-CD3 monoclonal antibody blinatumomab and with hypomethylating agent azacytidine plus the BCL-2 inhibitor venetoclax. She then underwent hematopoietic stem cell transplantation from HLA-identical sibling donor and she is still in complete remission after 9 months. To the best of our knowledge, there are no cases in the literature describing MPAL after autologous transplant for MM. Our patient was treated with blinatumomab and venetoclax and achieved complete remission 9 months from allogeneic transplant. The mechanism underlying the development of MPAL is not completely understood and therapies are still lacking. In this context the combination of blinatumomab, azacytidine and venetoclax successfully used in this patient may provide food for thought for further studies in this rare setting of patients.

Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia.

A case of an early-relapsed high-risk T-ALL with high BCL-2 expression on leukemic blasts was successfully treated with decitabine and venetoclax, achieving a CR. We suggest decitabine and venetoclax should be synergistic in BCL2-positive ALL.

Long-Term Safety of Rapid Daratumumab Infusions in Multiple Myeloma Patients.

Multiple myeloma survival has significantly improved in recent years, due to novel agents that are available for treatment. The anti-CD38 monoclonal antibody Daratumumab is particularly efficient for patients with relapse/refractory disease, and many studies have shown its unprecedented efficacy also as a first treatment. However, to avoid the incidence of infusion reactions, long infusion schedules of 8 h at first dose and 4 h in the following doses are required, which can reduce the compliance of patients and health care professionals. A reduced infusion time of 90 min has been reported previously, but data are missing on the prolonged safety of this over time as well as the efficacy of this approach. In this work, we investigate the safety of 484 rapid Daratumumab infusions given early after the second dose over a 22 months period in 39 myeloma patients.

Immunological Outcome in Haploidentical-HSC Transplanted Patients Treated with IL-10-Anergized Donor T Cells.

T-cell therapy after hematopoietic stem cell transplantation (HSCT) has been used alone or in combination with immunosuppression to cure hematologic malignancies and to prevent disease recurrence. Here, we describe the outcome of patients with high-risk/advanced stage hematologic malignancies, who received T-cell depleted (TCD) haploidentical-HSCT (haplo-HSCT) combined with donor T lymphocytes pretreated with IL-10 (ALT-TEN trial). IL-10-anergized donor T cells (IL-10-DLI) contained T regulatory type 1 (Tr1) cells specific for the host alloantigens, limiting donor-vs.-host-reactivity, and memory T cells able to respond to pathogens. IL-10-DLI were infused in 12 patients with the goal of improving immune reconstitution after haplo-HSCT without increasing the risk of graft-versus-host-disease (GvHD). IL-10-DLI led to fast immune reconstitution in five patients. In four out of the five patients, total T-cell counts, TCR-Vß repertoire and T-cell functions progressively normalized after IL-10-DLI. These four patients are alive, in complete disease remission and immunosuppression-free at 7.2 years (median follow-up) after haplo-HSCT. Transient GvHD was observed in the immune reconstituted (IR) patients, despite persistent host-specific hypo-responsiveness of donor T cells in vitro and enrichment of cells with Tr1-specific biomarkers in vivo. Gene-expression profiles of IR patients showed a common signature of tolerance. This study provides the first indication of the feasibility of Tr1 cell-based therapy and paves way for the use of these Tr1 cells as adjuvant treatment for malignancies and immune-mediated disorders.

Plerixafor and autologous stem cell transplantation: impressive result in a chemoresistant testicular cancer patient treated with high-dose chemotherapy.

Plerixafor, a CXCR4 antagonist, induces the rapid release of hematopoietic progenitor stem cells from the bone marrow into peripheral blood; it is approved for autologous hematopoietic progenitor stem cell mobilization in multiple myeloma and non-Hodgkin's lymphoma patients. We report the case of a 34-year-old patient with metastatic testicular embryonal carcinoma who was extensively and in vain pretreated with chemotherapy and failed to mobilize an adequate number of hematopoietic progenitor stem cells following high-dose chemotherapy, with the support of granulocyte colony-stimulating factors. After a cycle of high-dose cyclophosphamide associated with granulocyte colony-stimulating factors, plerixafor was administered to the patient, with the clinical evidence of an increase in hematopoietic progenitor stem cells in the peripheral blood. The patient achieved a complete engraftment following two cycles of high-dose chemotherapy (paclitaxel, ifosfamide, carboplatin, etoposide), with the support of hematopoietic progenitor stem cells; the patient showed discrete tolerability to the treatment. At biochemical control, the ß-human chorionic gonadotropin value decreased from 86 to less than 1.2 mUI/ml and total body PET-CT scan showed a complete response to chemotherapy. According to this experience, we believe that in patients with advanced germ cell cancer, it is essential to explore the possibility of the use of high-dose chemotherapy to induce a stable and permanent response; in this context, plerixafor, with the support of granulocyte colony-stimulating factors, may be an innovative option for satisfactory mobilization during high-dose chemotherapy protocols.

Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation.

The extensive exploitation of the antitumor effect of donor lymphocytes infused after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is limited by the risk of graft-versus-host disease (GvHD). To overcome this limitation, we investigated the therapeutic potential of donor lymphocytes engineered with the suicide gene thymidine kinase of herpes simplex virus (TK) in 23 patients experiencing recurrence of hematologic malignancies after allo-HSCT. Long-term follow-up of infused patients included analysis of engraftment of genetically engineered lymphocytes, in vivo assessment of antitumor effect, and control of GvHD by ganciclovir. All 17 patients evaluable for engraftment and graft-versus-leukemia (GvL) had circulating TK(+) cells detectable beginning at a median time of 18 days. Eleven patients (65%) experienced a substantial clinical benefit resulting in 6 (35%) complete remissions and 5 (29%) partial responses. The antitumor effect tightly correlated with the in vivo expansion of TK(+) cells. Seven patients received ganciclovir, resulting in elimination of TK(+) cells and effective and selective treatment of GvHD. Immunization against HSV-TK was observed in 7 patients but did not preclude an effective GvL. These data validate the feasibility, safety, and efficacy of TK(+) cells in the context of allografting and represent the basis for a broader application of this technology.

Qualitative and quantitative polymerase chain reaction detection of the residual myeloma cell contamination after positive selection of CD34+ cells with small- and large-scale Miltenyi cell sorting system.

The purging efficacy of the Miltenyi sorting system was evaluated by qualitative and TaqMan quantitative polymerase chain reaction (PCR) in myeloma patients, using immunoglobulin genes. After small-scale selection, qualitative PCR showed that in 6 of 12 leukaphereses myeloma cells were no longer detectable. Envisaging a possible clinical application, the leukaphereses from three patients underwent large-scale selection. Qualitative PCR showed that myeloma cells were still detectable. Quantitative PCR, performed in two patients, showed a tumour depletion of 1 and 2 logs respectively. Although numbers are small, the promising results obtained with small-scale selection were not reproduced in large-scale experiments.