BACKGROUND T-cell large granular lymphocytic leukemia (T-LGL) is a rare hematological malignancy that currently has no standard therapy. Immunoglobulin heavy chain amyloidosis (AH) involving the kidney is a rare condition and the pathology, diagnosis, clinical characteristics, and prognosis are becoming understood. This report is of a rare case of T-LGL associated with renal AH and discusses the approach to management. CASE REPORT A 57-year-old woman presented with symptoms of fatigue and she had proteinuria. A diagnosis of T-LGL associated with renal AH was made, which is an association that has not been previously reported in the literature. Given the dysregulation of her immune function due to her underlying T-LGL and her comorbidities, treatment options were limited. She was clinically stable and was initially observed. After one year, her symptoms of fatigue became worse, and her proteinuria increased. Treatment was initiated with the triple drug combination of bortezomib, cyclophosphamide, and dexamethasone (CyBorD) with consideration for future hematopoietic stem cell transplantation (HSCT). Her clinical condition improved, with a reduction in proteinuria. CONCLUSIONS A rare case of T-LGL and renal AH is presented. Currently, there is no standard therapy for T-LGL and AH amyloidosis, and the approach, in this case, was to manage the patient initially with CyBorD triple chemotherapy.

Background

The monoclonal antibody daratumumab, approved for treating myeloma, targets CD38, a protein on myeloma and also on CD34+ hematopoietic progenitor cells. Because mobilized CD34+ cells are critical for stem cell transplant, we investigated the in vitro activity of daratumumab on mobilized CD34+ cells from myeloma patients with no prior exposure to daratumumab.

Methods

We determined the number of CD38 molecules per CD34+ cell, and whether daratumumab bound to CD34+ cells, whether C1q bound to daratumumab-coated CD34+ cells and whether daratumumab-related complement-dependent cytotoxicity (CDC) occurred. We also examined CD34+ cell progenitor cell colony capacity in assays with pre-plating incubation of CD34+ cells with daratumumab alone or with daratumumab and the CD59 inhibitory antibody BRIC229, and also assessed CD34+ cell responses to increasing doses of daratumumab in caspase 3/7 activity assays.

Results

Although 75% of mobilized CD34+ cells co-express CD38, CD38 was minimally present on CD34+ cells compared to Daudi and KG-1 controls, C1q did not bind to daratumumab-coated CD34+ cells, and CDC did not occur. CD34+ cells incubated in complement-rich human serum with daratumumab alone or with daratumumab and BRIC229, and then plated in progenitor cell assays, produced similar numbers of colonies as controls. In progenitor cell assays with cryopreserved or fresh unselected or CD34-selected cells, daratumumab did not affect progenitor cell capacity, and in caspase 3/7 activity assays CD34+ cells were not affected by increasing doses of daratumumab.

Conclusion

In vitro, daratumumab is not toxic to mobilized CD34+ progenitor cells from myeloma patients.

BACKGROUND

In the setting of allogeneic stem cell transplantation (alloSCT), infusing natural killer (NK) cells from a major histocompatibility complex (MHC) mismatched donor can mediate an anti-leukemic effect. Graft versus tumor (GvT) effect following autologous stem cell transplantation (ASCT) may result in less disease relapse.

STUDY DESIGN AND METHODS

We performed a phase I clinical trial to assess the safety and feasibility of infusing distantly processed donor NK enriched mononuclear cell (NK-MC) infusions from a MHC haplotype mismatched (haploidentical) donor to patients who recently underwent ASCT for a hematologic malignancy. On day 1, peripheral blood mononuclear cells (MC) were obtained by steady-state leukapheresis and sent from Boston to the Production Assistance for Cellular Therapies (PACT) facility at the University of Minnesota, where immunomagnetic depletion of CD3 cells was performed on day 2. NK-MC product were then returned to Boston on day 2 for infusion on day 3. Toxicity, cellular product characteristics and logistic events were monitored.

RESULTS

At a median of 90 days (range, 49–191) following ASCT, thirteen patients were treated with escalating doses of NK-MC per kg from 10⁵ to 2 ×10⁷. Adverse effects included grade 2 rigors and muscle aches, but no grade 3 or 4 events, and no GvHD or marrow suppression. One air courier delay occurred. NK-MC products were viable with cytotoxic activity after transport.

CONCLUSION

CD3-depleted, MHC mismatched allogeneic NK-MC infusions can be safely and feasibly administered to patients after ASCT following distant processing and transport, justifying further development of this approach.