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Background and Aims A 21 year old boy with a diagnosis of Autosomal Recessive Polycystic Kidney Disease and Caroli disease reached a final stage of chronic kidney disease (CKD) and started haemodialysis. Method After 3 years in haemodialysis he underwent a kidney transplant from a cadaveric donor. His transplanted kidney worked fairly well until the patients was 31 year old when he developed graft dysfunction (serum creatinine from 2.7 to 5 mg/dL in a very short period). There was a concomitant increase in serum phosphate levels (8.3 mg/dl) and iPTH that progressively increased to 1032 pg/ml despite a traditional therapy. Results At age 32, the patient returned to haemodialysis treatment thrice weekly with a concomitant a progressive worsening of hyperparathyroidism with bone pain . Cinacalcet at a dosage of 30 mg daily treatment was initiated, then it was increased to 120 mg daily without any benefit. Two years later, being the clinical situation without any improvement and being the patient scarcely compliant to the therapy and because a further enlargement of parathyroid glands was observed, a Parathyroidectomy (PTX) was advised. Nevertheless, PTX was not performed because of patient’s refusal. Furthermore, despite Erythropoietic Stimulating Agent (ESA) therapy, he developed severe anemia that required regular and frequent blood transfusions. iPTH increased to 4500 pg/ml [Fig.1] with a parallel rise in alkaline phosphatase >600 UI/L [Fig.2]. A Computed Tomography scan showed multiple bone-thickening lesions. He thus initiated Etelcalcetide 5 mg e.v. 3 times a week, after the HD session but without any benefit. The dosage was then increased to 7.5 mg but the patient gradually became frail and developed pancytopenia and low-grade fever. Hematological evaluation with bone marrow biopsy was performed in December 2019. Bone marrow histology showed severe fibrosis [Myelofibrosis (MF) grade 3] with normal bone marrow cytogenetics. Blood samples for mutations in JAK-2, CALR, and MPL and BCR-ABL rearrangement were negative. There was no evidence for a myeloproliferative neoplasm (MPN) or metastatic lesions. During the following months, while on a 7,5 mg dose of etalcalcetide, there was a gradual reduction in iPTH [Fig.1] and serum alkaline phosphatase [Fig.2], up to 500 pg/dl and 200 IU/L respectively. The patient developed asymptomatic, often severe, hypocalcemia which was managed with therapy. The patient’s clinical conditions gradually improved, anemia responded to lower doses of ESAs. A bone marrow biopsy was repeated after one year (December 2020) and it showed a reduction in fibrosis (MF grade varying from 1-2). Then etelcalcetide dosage was reduced while serum calcium and phosphate levels were in the normal limit. Conclusion Myelofibrosis secondary to renal osteodystrophy is an uncommon complication. It has been rarely reported and usually is associated with primary hyperparathyroidism. Marrow fibrosis and pancytopenia is related to the excessive iPTH that upregulates production of cytokines and paracrine factors in the bone marrow (IL-1a, IL-6, FNF-a, TGF–b, and platelet-derived growth factor) and it has an important stimulatory effect on fibroblast proliferation. It is known that surgical parathyroidectomy is associated with a reduction of bone marrow fibrosis in primary hyperparathyroidism. To our knowledge, this is probably the first case of tertiary hyperparathyroidism in which the effect of etelcalcetide is comparable to parathyroidectomy as far as on calcium-phosphate balance, and a significant improvement in bone marrow fibrosis and hemoglobin. In conclusion, etelcalcetide at least in this patient seems as effective as PTX on bone balance, bone marrow and anemia.

Tumor immunotherapy holds great promise in controlling multiple myeloma (MM) and may provide an alternative treatment modality to conventional chemotherapy for MM patients. For this reason, a major area of investigation is the development of cancer vaccines to generate myeloma-specific immunity. Several antigens that are able to induce specific T-cell responses are involved in different critical mechanisms for cell differentiation, inhibition of apoptosis, demethylation and proliferation. Strategies under development include infusion of vaccine-primed and ex vivo expanded/costimulated autologous T cells after high-dose melphalan, genetic engineering of autologous T cells with receptors for myeloma-specific epitopes, administration of dendritic cell/plasma cell fusions and administration expanded marrow-infiltrating lymphocytes. In addition, novel immunomodulatory drugs may synergize with immunotherapies. The task ahead is to evaluate these approaches in appropriate clinical settings, and to couple them with strategies to overcome mechanisms of immunoparesis as a means to induce more robust clinically significant immune responses.

Despite recent treatments, such as bortezomib, thalidomide, and lenalidomide, therapy of multiple myeloma (MM) is limited, and MM remains an incurable disease associated with high mortality. The outcome of patients treated with cytotoxic therapy has not been satisfactory. Therefore, new therapies are needed for relapsed MM. A new anticancer strategy is the use of monoclonal antibodies (MoAbs) that represent the best available combination of tumor cytotoxicity, environmental signal privation, and immune system redirection. Clinical results in patients with relapsed/refractory MM suggest that MoAbs are likely to operate synergistically with traditional therapies (dexamethasone), immune modulators (thalidomide, lenalidomide), and other novel therapies (bortezomib); in addition, MoAbs have shown the ability to overcome resistance to these therapies. It remains to be defined how MoAb therapy can most fruitfully be incorporated into the current therapeutic paradigms that have achieved significant survival earnings in patients with MM. This will require careful consideration of the optimal sequence of treatments and their clinical position as either short-term induction therapy, frontline therapy in patients ineligible for ASCT, or long-term maintenance treatment.

Background: Diagnosis of a prefibrotic state (MF0) presents histological diagnostic difficulties. MF0 has a worst prognostic impact than Essential Thrombocythemia (TE) as regard the thrombotic risk and a higher risk towards Idiopathic Myelofibrosis (MI) and acute leukemia evolution. For this reason it is very useful to identify this group of patients. Aims: The aim of this study was to evaluate clinical and hematological impact of the mutational status in patients with an MF0 diagnosis. Methods: A retrospective chart review was performed from January 2010 to July 2015 in a single center in 317 patients affected by Ph negative chronic myeloproliferative neoplasms. Polycythemia vera cases were excluded. Thirty-three patients have been classified as MF0 on the base of the bone marrow histological examination. Onset features include cytogenetics, blood counts, peripheral CD34-positive cells, spleen and liver size, thrombotic events (prior to and post-diagnosis) and thrombotic risk. Fragment analysis was performed to study exon 9 CALR mutation, Real-time PCR was applied for exon 14 JAK2 V617F mutation and Sanger sequencing was used to identify exon 10 MPL mutations for 505 and 515 codons. According to genetic results, patients were identified into four groups according to a positivity for JAK2, MPL, CALR and for triple negativity. Results: The 33 patients with MF0 were: 11 (33%) JAK2 positive, 10 (30%) CALR positive, (10) 30% triple negative and 2 (7%) MPL positive. The latter group was not further considered for analysis due to the low number of cases. Eighty percent of CALR positive patients had a deletion on the exon 9 of the gene (8 del52bp and 2 del46bp), while 20% had the type 2 mutation (ins5bp). The average of JAK2 allelic burden was 20%. The 3 groups of patients were comparable for age, white blood counts and hemoglobin values. There was a female prevalence (23 vs 10 males). Platelet count was higher (median 875.500 103 µl, interquartile range 303.000 103 µl , p = 0.008) in CALR positive patients compared to JAK2 positive (median 569.000 103 µl, interquartile range 433.000 103 µl) and to triple negative patients (median PLT count 629.500 103 µl, interquartile range 378.250 103 µl). Noteworthy, bone marrow cytogenetic exam was normal in all patients. JAK2 positive patients had a larger spleen compared to the other two groups. Pre-diagnosis thrombotic events were exclusive for JAK2 positive patients and absent in the other groups. Triple negative patients do not have a negative prognostic impact for the thrombotic risk. Conclusions: CALR deletion could be considered as an MF0 marker and should be included in diagnostic work-up. JAK2 positivity in MF0 is associated with a high thrombotic risk. Disclosures No relevant conflicts of interest to declare.