Myeloma and pregnancy: strange bedfellows? Khot, Amit S.; Prince, H. Miles; Harrison, Simon J. ...
Leukemia & lymphoma,
04/2014, Letnik:
55, Številka:
4
Journal Article
Recenzirano
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The discovery of a structurally novel, orally bioavailable series of calcium sensing receptor negative allosteric modulators is described.
The design and profile of a series of zwitterionic calcium ...sensing receptor negative allosteric modulators is described. Evaluation of key analogues using a rat model demonstrate a robust response, significantly improved potency over ronacaleret and have the potential as an oral, anabolic treatment for osteoporosis.
Abstract 1862
Multiple Myeloma (MM) and its treatment are associated with impaired humoral and cellular immunity (CI). Lenalidomide (Len) is thought to mediate its anti-MM effect in part via ...stimulation of in vivo T cell, NK cell and NKT cell activity. However, as we have previously demonstrated (Hsu et al, Blood, 2011;117:1605), the immunostimulatory effects of Len are substantially abrogated by co-administration of high doses of Dexamethasone (Dex). It is unknown whether the efficacy of the Len/Dex induction regimen is maintained in newly diagnosed MM if the dose of Dex is lowered to preserve CI. In a prospective study (PMCC HREC #05/56), we examined both anti-MM responses and CI using a regimen of low dose Len and Dex induction followed by consolidation with autologous stem cell transplant (ASCT) in previously untreated patients with MM.
Twenty patients were enrolled. Induction therapy was with four 28 day (d) cycles of Len 15 mg d1 − 21 and Dex 20 mg weekly followed by hematopoietic stem cell (HSC) mobilization with cyclophosphamide 2 – 4 gm/m2 and G-CSF 10mcg/kg/day, and a melphalan 140 – 200mg/m2 conditioned ASCT. Maintenance with Rev 25mg d1-21 of a 28d cycle was commenced on d21-35 post ASCT until progression. Interim assessments of response were made post-induction, post-ASCT and on 31/05/2011 using IMWG uniform response criteria. Assessments of CI were undertaken at enrolment and again at the end of 4 cycles of induction by flow cytometric analysis of peripheral blood lymphocyte subsets (CD19+, CD3+, CD4+, CD8+, CD4+/CD25+/CD127+ Treg, CD3−/ CD16+/CD56+ NK cells), T cell proliferation to allogeneic stimulators (ratio 1:1) in a 7d mixed lymphocyte reaction (MLR) and analysis of NK function by cytotoxicity against K562 targets. All data were compared to age-matched controls, and analysed for statistical significance using a student T-test.
All patients have completed induction and ASCT. Median age=57.5 yrs, (range 44 – 70); male= 15; IgG = 10, IgA = 6 and light chain = 4. Stage at enrolment ISS1 = 9, ISS2 = 9 and ISS3 = 2. Median harvested CD34+ cells=10.8×106 /kg (range 4.9 – 40.6). The median number of CD34+ cells infused = 4.8×106 / kg (range 2.9 – 11.5) and median time to recovery of neutrophils > 0.5 ×109/L and platelets > 20 ×109/L was 12d (range 9 – 18) and 11d (range 8 – 25) respectively. The post-induction, overall response rate was 85%, very good partial response (VGPR)=20%, partial response (PR)= 65%, stable disease =5%, and 10% were refractory. Post-autograft responses improved to complete response (CR)=10%, VGPR= 40% and PR=35%. At a median follow-up of 17 months (range 5 – 29 months), the best response achieved to date is 35% CR, 25% VGPR and 30% PR (Fig 1). Immunology: CI data is available on 19 patients. Compared-to age matched controls, patients at enrolment had reduced CD3+ (p≤0.05), CD4+ (p≤0.01) (Fig 2)and Treg (P≤0.01) numbers and reduced NK cell function (p<0.05); however CD8+ T cell, NK cell and B cell numbers were normal. Following four cycles of Len/Dex therapy, CD3+, CD4+ and Treg numbers all increased, but remained below those of normal controls. Conversely, circulating B lymphocyte numbers fell substantially (P≤0.01) and NK cell function remained significantly impaired (p<0.05) following induction therapy. However, functional analysis of CD3+ (Fig 3), CD4+ and CD8+ proliferation in an MLR at enrolment and following induction therapy was identical to that of controls. Display omitted Display omitted Display omitted
This novel treatment regimen of low dose Len and low dose Dex followed by ASCT in untreated patients with MM is associated with high response rates and successful HSC collection. The depth of response progressively improved following ASCT. Cellular immunology in MM patients at diagnosis shows specific reductions in CD4+ and Treg cell numbers, and NK cell function that is not rescued by Len therapy when co-administered with Dex, even at low doses, which induced a further reduction in CD19+ cells. However despite these deficiencies, preserved proliferative capacity of both CD4+ and CD8+ T-cells is seen at diagnosis and following this induction therapy, suggesting that with the low dose Len-Dex regimen, the immune environment is conducive to novel strategies that are aimed at inducing adaptive anti-MM immune responses.
Harrison:Celgene: Honoraria, Research Funding. Off Label Use: Low dose lenalidomide in newly diagnosed myeloma. Neeson:Celgene: Research Funding. Prince:Celgene: Honoraria, Research Funding.
Abstract 4180▪▪This icon denotes a clinically relevant abstract
High risk acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) may be amenable to immunotherapy with adoptive transfer of ...chimeric antigen receptor (CAR) T cells. However, persistence and generation of central memory (CM) are essential for ongoing clinical responses (Morgan et al Science 2006). Our prior work showed that the carbohydrate antigen LewisY (LeY) is expressed in 46% of AML patients (n=33) to varying degrees, making it a suitable and novel target for CAR therapy. In our phase I study, we have assessed the trafficking, persistence and functional capacity of CAR-T cells transduced with an anti-LeY chimeric receptor gene in high-risk patients with LeY positive AML or MDS.
The CAR comprised extracellular humanized scFv recognizing the LeY Ag, linked to an extracellular CD8 hinge region, a transmembrane and cytoplasmic CD28 and CD3 zeta signalling domain. The humanized anti- LeY scFv-CD28-ζ receptor vector was produced as described previously (Westwood J et al PNAS 2005). T cells, harvested from the patient, were transduced with LeY scFv-CD28-ζ pSAMEN retroviral vector. Bulk transduced T cells (LeY-T) were re-infused into the patient after lymphodepleting fludarabine chemotherapy. AML immunophenotyping and cytogenetics were used to monitor minimal residual disease (MRD). PB and BM samples were collected prior to and post CAR-T adoptive transfer. An optimized PCR assay (sensitivity 1:1e5) for the presence of the LeY transgene (TG) was performed on genomic DNA extracted from each sample. To measure both CAR-T cell functional polarization and persistence of CAR expression, PB or BM cells were co-cultured with a cell line expressing LeY (OVCAR-3), in the presence or absence of MHC class I or II blocking antibodies. Culture supernatant was collected at 24 hours and assessed by Luminex assay for Th1 (IFN-g, IL-2), Th2 (IL-4, IL-10), pro-inflammatory (IL-6, IL-17 and TNF) cytokines and TGF-b.
Five AML patients have been enrolled to date. Four patients have had sufficient CAR-T cells generated to provide doses of 0.5 × 109 −1.3 × 109T cells (transduced T cells: 8 – 30% of total T-cells) with a viability of 96.1– 98.5%. 2 patients (01 and 04) had progressive disease 1 and 2 months after infusion. 2 patients (02 and 05) remain in morphologic remission with stable cytogenetic MRD, 3 and 14 months post infusion.
Patients 01, 02 and 04 all had LeY TG in PB and BM samples at all time points measured, up to day 49 in patient 01 (Figure 1) and up to 10 months in patient 02. In patient 04 LeY TG was also detected in a skin biopsy (day +6) of leukemic skin infiltrate. Display omitted
Co-culture supernatant cytokine analysis showed LeY-T cells from patient 01, 02 and 04 secreted high levels of IFN-g (805.5 ± 198.9 pg/ml) and low levels of IL-2 (3.14 ± 0.65 pg/ml) prior to adoptive transfer. In contrast, post adoptive transfer, co-culture with OVCAR-3 cells, and MHC class I and II blocking antibody, induced these PB LeY-T cells to secrete IL-4 (24.13 ± 12.47pg/ml) and IL-10 (9.35 ± 0.44 pg/ml); no IFN-g or IL-2 was detected. This Th2 polarization of CAR-T cells was shown in PB samples taken at days 5 to 28 (patient 01), day 28 to 8 months (patient 02) and day 1 to day 28 (patient 04) post-adoptive transfer (Figure 2). In addition, when Th1/Th2 cytokines were measured in patient 02 PB and BM plasma, Th1 cytokines were detected immediately post-adoptive transfer (IFN-g=39 pg/ml, IL-2=8.6 pg/ml at peak); however these decreased to basal levels by day 3 (IFN-g=1.8 pg/ml) and day 2 (IL-2=2.6 pg/ml). The same trend in serum cytokines was observed for patient 01. Display omitted
Therefore, our studies reveal that, after adoptive transfer, LeY CAR-T cells persist in vivo, maintain their expression of the CAR, but show rapid polarization from a Th1 to a Th2 phenotype.
No relevant conflicts of interest to declare.
IL6 is important for the growth and survival of myeloma cells. This study evaluated blocking IL6 with siltuximab to delay the transition from high-risk smoldering multiple myeloma (SMM) to multiple ...myeloma.
In a randomized, double-blind, placebo-controlled, multicenter study, 85 patients with high-risk SMM were randomized to 15 mg/kg siltuximab (43 patients) or placebo (42 patients). The primary endpoint was 1-year progression-free survival (PFS) rate, based on IMWG CRAB criteria. Secondary endpoints included progressive disease indicator rate, PFS, and safety.
Median age was 62 years (range: 21-84); 57% were male and 87% had a baseline Eastern Cooperative Oncology Group score of 0. The 1-year PFS rate was 84.5% (siltuximab) and 74.4% (placebo). After a median follow-up of 29.2 months, 32.6% of PFS events occurred with siltuximab and 42.9% with placebo. Median PFS was not reached with siltuximab but was 23.5 months with placebo HR 0.50 (95% confidence interval, 0.24-1.04);
= 0.0597. The safety profile of siltuximab was comparable with placebo. Most adverse events in the siltuximab group were grade 2/3; the most common serious adverse events were infections/infestations, and renal/urinary disorders. Mortality was low in both groups (3 deaths in the siltuximab group and 4 in the placebo group).
Although this study did not meet the prespecified protocol hypothesis criteria, data suggest that siltuximab may delay the progression of high-risk SMM.
Introduction
Individuals diagnosed with acute lymphoid and myeloid malignancies are at significant risk of invasive fungal and bacterial infections secondary to their marked immunocompromised states ...with a significant high risk of mortality. The role of metabolic imaging with 18F‐Fluorodeoxyglucose (FDG) Positron Emission Tomography/Computed Tomography (PET/CT) has been increasingly recognized in optimizing the diagnosis of invasive infection, monitoring the response to therapy and guiding the duration of antimicrobial therapy or need to escalate to surgical intervention.
Methods
Two distinct cases of pulmonary co‐infection of rare fungal and bacterial pathogens are explored in severely immunocompromised individuals where FDG PET/CT aided both patients to make a full recovery and transition to HCT. The first case explores mixed Scedosporium apiospermum and Rhizomucor pulmonary infection on a background of T cell/myeloid mixed phenotype acute leukemia ultimately warranting long‐term antifungal therapy and lobectomy prior to HCT. The second case explores Fusarium and Nocardia pulmonary infection on a background of relapsed AML also warranting surgical resection with lobectomy and long‐term antimicrobials prior to transition to HCT.
Discussion
The cases highlight the utility of FDG PET/CT to support the diagnosis of infections, including the presence or absence of disseminated infection, and to provide highly sensitive monitoring of the infection over time. FDG PET/CT played a key role in directing therapy duration decisions and prompted the necessity for surgical intervention. Ultimately, the use of FDG PET/CT allowed for a successful transition to HCT highlighting its value in this clinical setting.
Conclusion
FDG PET/CT has an emerging role in the diagnostic and monitoring pathway for complex infections in high‐risk immunocompromised patients.
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