Survival and late effects of hematopoietic cell transplantation in patients with thalassemia major.

In this retrospective study, we evaluated long-term survival and late effects in 137 patients affected by thalassemia major (TM) who received an allogeneic hematopoietic cell transplantation (HCT). Median age at HCT was 10.1 years. After a median follow-up of 30 years, 114 (83.2%) patients are living and 108 (78.8%) are cured. The cumulative incidence of nonrelapse mortality and thalassemia recurrence was 9.5% at 1 year and 10.2% at 39 years respectively. The 39-years cumulative incidence of overall survival and disease-free survival were 81.4% and 74.5%. One hundred twenty-three patients who survived more than 2 years after HCT were evaluated for late effects concerning hematological disorders, iron burden, growth, obesity, diabetes mellitus, thyroid and gonadal function, eye, heart, liver, lung, kidney, gastrointestinal, neurologic and psychiatric system, osteoarticular system, secondary solid cancer (SSC), performance status, and Covid-19 infection. Fertility was preserved in 21 males whose partners delivered 34 neonates and 25 females who delivered 26 neonates. Fifteen cases of SSC were diagnosed for a 39-year cumulative incidence of 16.4%. HCT represents a definitive cure for the majority of TM patients at the price, however, of a non-negligible early and late mortality which in the long run affects survival and disease-free survival.

Tongue cancer following hematopoietic cell transplantation for Fanconi anemia.

OBJECTIVES: The aim of this retrospective study was to determine the incidence and the clinical outcome of tongue cancer (TC) in patients affected by Fanconi anemia (FA) who received an allogeneic hematopoietic cell transplantation (HCT). MATERIALS AND METHODS: The patient database from the Bone Marrow Transplant Center of Pescara was reviewed to enroll FA patients. Patients', donors', HCT's, and screening's data were collected as well to look for the incidence and the treatment of TC. RESULTS: Twelve patients affected by FA were identified. Three patients died for transplant-related causes. Five of nine surviving patients were diagnosed with TC at a median of 21.7 years since transplantation and at a median age of 32.10 years. Interestingly, no patient manifested graft-versus-host-disease (GvHD). The 28-year cumulative incidence function of TC was 46.9% (95% CI, 36.9-56.9%). Two patients were treated with chemotherapy alone, two patients were treated with surgery alone, and one with surgery followed by chemotherapy. Overall, 4 patients with TC showed a clinical course characterized by a marked aggressiveness of the tumor disease which led to death due to cancer progression between 2 and 13 months. One patient is surviving 8 months after diagnosis of TC. CONCLUSIONS: Our study confirms the high incidence of tumors and in particular tongue tumors in allotransplanted FA patients. A careful screening has to be life-long maintained. CLINICAL RELEVANCE: Considering the rarity of FA and the frailty of FA patients, this study may add important information for the cancer management of these patients.

Secondary oral cancer following hematopoietic cell transplantation.

The aim of this retrospective study was to determine the incidence and the clinical outcome of secondary oral cancer (SOC) and to assess potential risk factors in a large cohort of patients (n = 908), who received allogeneic hemopoietic cell transplantation (HCT) either for a malignant (n = 733) or nonmalignant hematologic disease (n = 175). The median follow-up of 438 transplant survivors was 17 years. Twelve patients developed SOC at a median of 13.5 years since HCT and at a median age of 47 years. The 35-year cumulative incidence function of SOC development was 3.47%. In univariate analysis, factors associated with increased incidence of SOC were reduced intensity conditioning and chronic graft-versus-host disease (cGvHD). On multivariate analysis, nonmalignant disease and duration of oral cGvHD ≥15 months were independent risk factors for SOC development. Nonmalignant disease recipients had 3.94× higher than expected rate of SOC (95% confidence interval, 1.50-10.39%, p = 0.0055). Recipients whose oral cGvHD persisted for more than ≥15 months had 58.6× higher than expected rate of SOC (95% confidence interval, 13.3-258.1%), p < 0.0001). This study demonstrates that oral cGvHD and a diagnosis of nonmalignant hematologic disease are strong risk factors in the SOC development.

Pomalidomide-Responsive Extramedullary Myeloma Relapsed after Allogeneic Hematopoietic Transplant and Refractory to Multiple Lines of Chemotherapy.

Patients who experience extramedullary relapses (EMR) of multiple myeloma (MM) have an adverse prognosis, also in this era of novel agents like proteasome inhibitors and immunomodulatory drugs. We describe the case of an MM patient with EMR at 2 different sites after allogeneic stem cell transplantation. EMR was refractory to bortezomib, anthracycline, and bendamustine, but the patient achieved long-term complete remission (4 years) with pomalidomide and dexamethasone. This supports the hypothesis that this could be due to the graft-versus-myeloma effect during therapy enhanced by pomalidomide.

The adipose organ and multiple myeloma: Impact of adipokines on tumor growth and potential sites for therapeutic intervention.

In addition to its capacity to store lipids the adipose tissue is now identified as a real organ with both endocrine and metabolic roles. Preclinical results indicate that modifying adipose tissue and bone marrow adipose tissue (BMAT) could be a successful multiple myeloma (MM) therapy. BMAT interrelates with bone marrow cells and other immune cells, and may influence MM disease progression. The BM adipocytes may have a role in MM progression, bone homing, chemoresistance, and relapse, due to local endocrine, paracrine, or metabolic factors. BM adipocytes isolated from MM subjects have been shown to increase myeloma growth in vitro and may preserve cells from chemotherapy-induced apoptosis. By producing free fatty acids and emitting signaling molecules such as growth factors and adipokines, BM adipocytes are both an energy font and an endocrine signaling factory. This review should suggest future research approaches toward developing novel treatments to target MM by targeting BMAT and its products.

Nanobodies and Cancer: Current Status and New Perspectives.

Reducing the dimension of antigen-binding proteins to an only immunoglobulin domain has been one of the objectives of antibody manufacturing. Heavy chain antibodies were encountered while attempting to separate the blood serum proteins of dromedaries. Later the term "nanobodies" (Nbs) was introduced. The advantageous features of Nbs comprise little immunogenicity, stability at low/high pH, capacity to target antigens that are less antigenic, and, lastly, easy capability to be used for therapy against tumor cells. Presently, Nbs have been used for several medical and biotechnological purposes. Numerous Nb-derived formats have been positively proved useful for targeting drug delivery, and bioimaging.

Adoptive immunotherapy for hematological malignancies: Current status and new insights in chimeric antigen receptor T cells.

Hematological malignancies frequently express cancer-associated antigens that are shared with normal cells. Such tumor cells elude the host immune system because several T cells targeted against self-antigens are removed during thymic development, and those that persist are eliminated by a regulatory population of T cells. Chimeric antigen receptor-modified T cells (CAR-Ts) have emerged as a novel modality for tumor immunotherapy due to their powerful efficacy against tumor cells. These cells are created by transducing genes-coding fusion proteins of tumor antigen-recognition single-chain Fv connected to the intracellular signaling domains of T cell receptors, and are classed as first-, second- and third-generation, differing on the intracellular signaling domain number of T cell receptors. CAR-T treatment has emerged as a promising approach for patients with hematological malignancies, and there are several works reporting clinical trials of the use of CAR-modified T-cells in acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, lymphoma, and in acute myeloid leukemia by targeting different antigens. This review reports the history of adoptive immunotherapy using CAR-Ts, the CAR-T manufacturing process, and T cell therapies in development for hematological malignancies.