Despite its promising outcomes, anti-BCMA chimeric antigen receptor T cell therapy (CAR-T) is the most expensive myeloma treatment developed to date, and its cost-effectiveness is an important issue. ...This study aimed to assess the cost-effectiveness of anti-BCMA CAR-T compared to standard antimyeloma therapy in patients with relapsed/refractory multiple myeloma. The model included myeloma patients in Japan and the United States who have received ≥3 prior lines of antimyeloma therapy, including immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. A Markov model was constructed to compare the CAR-T strategy, in which patients receive either idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel) followed by 3 lines of multiagent chemotherapy after relapse, and the no CAR-T strategy, in which patients receive only chemotherapy. Data from the LocoMMotion, KarMMa, and CARTITUDE-1 trials were extracted. Several assumptions were made regarding long-term progression-free survival (PFS) with CAR-T. Extensive scenario analyses were made regarding regimens for no CAR-T strategies. The outcome was an incremental cost-effectiveness ratio (ICER) with willingness-to-pay thresholds of ¥7,500,000 in Japan and $150,000 in the United States. When a 5-year PFS of 40% with cilta-cel was assumed, the ICER of the CAR-T strategy versus the no CAR-T strategy was ¥7,603,823 per QALY in Japan and $112,191 per QALY in the United States over a 10-year time horizon. When a 5-year PFS of 15% with ide-cel was assumed, the ICER was ¥20,388,711 per QALY in Japan and $261,678 per QALY in the United States over a 10-year time horizon. The results were highly dependent on the PFS assumption with CAR-T and were robust to changes in most other parameters and scenarios. Although anti-BCMA CAR-T can be cost-effective even under current pricing, a high long-term PFS is necessary.
Abstract
In the rituximab era, several large studies have suggested that full-dose rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) might be the best treatment for ...patients with diffuse large B-cell lymphoma (DLBCL) aged 60 years and older. However, it remains unclear whether this is also the case for those aged 70 years and older. Previously untreated patients with DLBCL aged 70 years and older (elderly) were treated with R-70%CHOP, and patients younger than 70 years (younger) were treated with full-dose R-CHOP every 3 weeks, for a total of 6-8 cycles. Complete remission (CR) rates in elderly versus younger patients were 75 vs. 78% (p = 0.7), respectively. The 3-year overall survival, event-free survival and progression-free survival of elderly versus younger patients were 58 vs. 78% (p < 0.05), 45 vs. 70% (p < 0.05) and 64 vs. 72% (p = 0.43), respectively. Severe adverse events were more frequent in the elderly, even with the dose reduction in that age group. Three-year PFS with R-70%CHOP for patients aged 70 years and older was not significantly worse than that with full-dose R-CHOP for younger patients, suggesting that R-70% CHOP might be a reasonable choice for patients with DLBCL aged 70 years and older, especially for those with comorbidities.
Abstract 3173
Deferasirox (DFX) is an oral iron chelator that enables effective chelation by once daily administration.Since the introduction of DFX, iron chelation therapy (ICT) for transfusional ...iron overload has attracted increased attention. It is known that excess iron increases oxidative stress and affects various organs, such as the liver, heart and endocrine glands, negatively. Sufficient ICT can remove excess iron and improve organ dysfunction in iron-overloaded patients, and accumulating data has indicated that efficient ICT improves the survival of transfusion-dependent patients with myelodysplastic syndromes (MDS). Recently, we experienced a case of MDS with transfusional iron overload in which the hematopoietic data improved unexpectedly after administration of DFX without any other specific treatments (Okabe H et al. Rinsho Ketsueki, 2009). An increasing number of similar cases has been reported. This clinical observation indicates that iron overload could also affect the hematopoietic system unfavorably, via, as yet, unknown mechanisms.
We generated iron-overloaded mice to investigate how iron overload affects hematopoiesis in vivo. C57BL6 mice were injected with a total of 200 mg of iron dextran, intraperitoneally over 4 weeks. The iron-overloaded mice showed pigmented skin and hepatosplenomegaly, and histological examination showed excess iron deposition in the bone marrow, liver, spleen and heart. The serum and organ iron concentrations in these mice markedly increased. However, the iron-overloaded mice did not show any significant changes in peripheral blood counts or the proportion of immature hematopoietic cells in the bone marrow. To further examine the effects of excess iron on the biological functions of hematopoietic stem and progenitor cells (HSPCs), we performed bone marrow transplantation (BMT) assays. First, to assess the hematopoietic reconstitutional capacity of the HSPCs of iron-overloaded mice, we transplanted bone marrow cells (1×106 cells) from iron-overloaded mice or normal mice into lethally irradiated normal recipient mice along with the same number of normal competitor cells. We found no significant difference in hematopoietic reconstitution between the iron-overloaded donor cells and the normal donor cells, suggesting that the hematopoietic reconstitutional capacity of HSPCs in iron-overloaded mice is not significantly affected by iron. In contrast, when we transplanted bone marrow cells from normal mice (2×106 cells) into iron-overloaded recipients, hematopoietic recovery was significantly delayed, in particular platelet counts (at 2 weeks after BMT, normal recipients vs. iron-overloaded recipients, 63.4±9.4 vs. 18.7±4.7×104/μl, respectively, p<0.001). This indicates that excess iron disturbs the function of the bone marrow microenvironment and delays hematopoietic reconstitution. Microarray and quantitative RT-PCR analysis of non-hematopoietic bone marrow cells (CD45-/Ter119-) from the iron-overloaded mice demonstrated significant reductions in CXCL12, VCAM-1, Kit-ligand and IGF-1, which are important regulators of hematopoiesis. In addition, in the iron-overloaded mice, the serum concentration of erythropoietin and the expression level of thrombopoietin in the liver were also significantly reduced. Furthermore, increased oxidative stress levels were observed in the iron-overloaded liver and bone marrow.
We did not observe any direct effects of excessive iron on hematopoietic cells, but found significant impairment of the hematopoietic microenvironment in the bone marrow of iron-overloaded mice. These results suggest that oxidative stress induced by excess iron could disturb the hematopoiesis-supporting capacity of the bone marrow microenvironment by reducing the expression of many essential molecules.
No relevant conflicts of interest to declare.
Abstract 3643
Poster Board III-579
<Background and purpose>
c-Cbl is a ubiquitin E3 ligase and functions as a negative regulator for signals induced by various activated tyrosine kinases, by ...promoting ubiquitination and proteasomal degradation of these kinases. This inhibitory action is mainly mediated by the tyrosine kinase binding (TKB) and RING finger domains located in the NH3-terminal part of the molecule and these domains are evolutionally well-conserved from nematodes. But mammalian c-Cbl has a stretched structure toward the COOH-terminal end with putative tyrosine residues that can interact with p85 subunit of PI3-kinase, and several reports have denoted that this interaction may be important for cytoskeletal regulation. Recently, mutations of the c-cbl gene have been reported in hematopoietic malignancies, and regulation of hematopoietic stem/progenitor cells (HSPCs) by Cbl is attracting attention. Since it is well-known that cytoskeletal dysregulation is often associated with malignant transformation, in this study, we investigated cytoskeletal regulatory mechanisms mediated by Cbl in hematopoietic cells, using Cbl deficient mice.
To examine the migratory capacity of the HSPCs, lineage negative (Lin(-)) bone marrow cells were set in the Boyden Chamber assay for SDF-1 and fibronectin (FN) were performed. We found that Cbl deficient Lin(-) cells showed significantly decreased migration to these chemoattractants; the migration capacity of the Cbl deficient cells was one eighth for SDF-1 (p = 0.01) and one third for FN (p = 0.007), respectively, compared with the wild-type counterparts. Then, to evaluate in vivo homing ability to the bone marrow microenvironment, transplantation assays were performed. We transplanted 2.5 × 10e6 of Lin(-) HSPCs from Cbl deficient or wild-type Ly5.2 mice into sublethally irradiated wild-type Ly5.1 mice. Three hours after transplantation, chimerism of the transplanted Ly5.2 cells in the bone marrow was examined, and we found that the number of transplanted cells was significantly smaller in Cbl deficient cells, showing that homing capacity of HSPCs in Cbl deficient mice was impaired. Moreover, when we administered G-CSF to Cbl deficient mice, a significantly larger number of Lin(-) Sca1(+) c-Kit(+) cells were mobilized from the bone marrow (p = 0.01), indicating that in Cbl deficient mice, mobilization of HSPCs by G-CSF was also affected. In bone marrow cells or Lin(-) HPSCs of Cbl deficient mice, activity of Rac, a member of small G-protein GTPases, was significantly decreased (p = 0.002). These data ware supported by the experiments with embryonic fibroblast; Rac activities induced by FN stimulation were weaker in Cbl deficient fibroblasts than wild-type ones, and Cbl deficient fibroblasts showed impaired actin rearrangement.
We found that Cbl deficient HSPCs showed impaired migration activities to chemoattractants and altered homing and mobilization to and from the bone marrow. Furthermore, Cbl deficient cells had impaired activation of Rac. Currently, little is known about the relationship between Cbl-mediated signals and cytoskeletal regulator Rac, and in this study, we found that Cbl is a positive regulator of Rac activity in the bone marrow hematopoietic cells. Rac activity is reported to be necessary for homing and retention of HSPCs in the bone marrow microenvironment, and our results indicate that interaction of HSPCs with the bone marrow microenvironment, e.g. trafficking of these cells, is regulated by Cbl via Rac GTPase signals.
No relevant conflicts of interest to declare.
Myelodysplastic syndrome (MDS) is a slowly progressing hematologic malignancy associated with a poor outcome. Despite the relatively high incidence of MDS in the elderly, differentiation of MDS from ...de novo acute myeloid leukemia (AML) still remains problematic. Identification of genes expressed in an MDS-specific manner would allow the molecular diagnosis of MDS. Toward this goal, AC133 surface marker–positive hematopoietic stem cell (HSC)-like fractions have been collected from a variety of leukemias in a large-scale and long-term genomics project, referred to as “Blast Bank,” and transcriptome of these purified blasts from the patients with MDS were then compared with those from AML through the use of oligonucleotide microarrays. A number of genes were shown to be expressed in a disease-specific manner either to MDS or AML. Among the former found was the gene encoding the protein Delta-like (Dlk) that is distantly related to the Delta-Notch family of signaling proteins. Because overexpression of Dlk may play a role in the pathogenesis of MDS, the disease specificity of Dlk expression was tested by a quantitative “real-time” polymerase chain reaction analysis. Examination of the Blast Bank samples from 22 patients with MDS, 31 with AML, and 8 with chronic myeloid leukemia confirmed the highly selective expression of the Dlk gene in the individuals with MDS. Dlk could be the first candidate molecule to differentiate MDS from AML. The proposal is made that microarray analysis with the Blast Bank samples is an efficient approach to extract transcriptome data of clinical relevance for a wide range of hematologic disorders.
Myelodysplastic syndrome (MDS) is a clonal disorder of haematopoietic stem cells. Despite the high incidence of MDS in the elderly, effective treatment of individuals in its advanced stages is ...problematic. DNA microarray analysis is a potentially informative approach to the development of new treatments for MDS. However, a simple comparison of ‘transcriptomes’ of bone marrow mononuclear cells among individuals at distinct stages of MDS would result in the identification of genes whose expression differences only reflect differences in the proportion of MDS blasts within bone marrow. Such a ‘population shift’ effect has now been avoided by purification of haematopoietic stem‐like cells that are positive for the cell surface marker AC133 from the bone marrow of healthy volunteers and 30 patients at various stages of MDS. Microarray analysis with the AC133+ cells from these individuals resulted in the identification of sets of genes with expression that was specific to either indolent or advanced stages of MDS. The former group of genes included that for PIASy, which catalyses protein modification with the ubiquitin‐like molecule SUMO. Induction of PIASy expression in a mouse myeloid cell line induced apoptosis. A loss of PIASy expression may therefore contribute directly to the growth of MDS blasts and stage progression.
Multiple myeloma (MM) is incurable, mainly because of cell adhesion-mediated drug resistance (CAM-DR). In this study, we performed functional screening using shRNA to define the molecule(s) ...responsible for CAM-DR of MM. Using 4 bona fide myeloma cell lines (KHM-1B, KMS12-BM, RPMI8226, and U266) and primary myeloma cells, we identified CD29 (b1-integrin), CD44, CD49d (a4-integrin, a subunit of VLA-4), CD54 (ICAM-1), CD138 (syndecan-1) and CD184 (CXCR4) as major adhesion molecules expressed on MM. Short hairpin RNA-mediated knockdown of CD49d but not CD44, CD54, CD138, and CD184 significantly reversed CAM-DR of myeloma cells to bortezomib, vincristine, doxorubicin, and dexamethasone. Experiments using blocking antibodies yielded almost identical results. Bortezomib was relatively resistant to CAM-DR because of its ability to specifically down-regulate CD49d expression. This property was unique to bortezomib and was not observed in other anti-myeloma drugs. Pretreatment with bortezomib was able to ameliorate CAM-DR of myeloma cells to vincristine and dexamethasone. These results suggest that VLA-4 plays a critical role in CAM-DR of MM cells. The combination of bortezomib with conventional anti-myeloma drugs may be effective in overcoming CAM-DR of MM.
Deferasirox (DFX) is a newly developed oral iron chelator that enables effective chelation with once daily administration. We describe here a case of transfusional-iron overloaded patient who ...experienced hematopoietic recovery after DFX administration. A 75-year-old woman with iron overload, who had been diagnosed with MDS (RCMD) and had received a transfusion of red blood cells and platelets regularly for 3 years, enrolled in the phase I clinical trial of ICL670 (DFX) in Japan. DFX administration steadily decreased her serum ferritin levels and chelated overloaded iron effectively. Interestingly, a year after initiation of the trial, she needed fewer blood transfusions, and no more transfusions after the 17th month of the trial. Even after suspending transfusions, her hemoglobin level and platelet count increased continuously, and she now has stable disease without blood transfusions. She has not received any specific treatment for MDS during this period. Examination of the bone marrow aspirates in the 35th month revealed dysplastic cells, indicating no remarkable change in the state of MDS. This case suggests that excess iron hampers hematopoiesis and that adequate iron chelation may improve hematological data in some iron-overloaded patients.
Determination of the percentage of myeloblasts in bone marrow is important for the evaluation of acute myeloblastic leukemia (AML) and related disorders. Using flow cytometry with a CD45-blast gate ...(FCM/CD45), 226 bone marrow aspiration samples serially collected from 71 patients with de novo AML were analyzed. Bone marrow smears were evaluated independently by pathologists who did not know the corresponding flow cytometric data in advance. Patients received remission induction followed by consolidation. The CD33+ cell percentages evaluated by FCM/CD45 were strongly correlated to the myeloblast percentages determined by microscopic examination (r=0·8360, p<0·001). When only samples containing leukemic cells demonstrated by chromosomal or fluorescence in situ hybridization (FISH) analysis after induction were evaluated, positive correlations were found between CD33+ cell percentages determined by FCM/CD45 and myeloblast percentages determined by morphology (r=0·672, p<0·001). The identification of CD33+ cells by FCM/CD45 is useful for the evaluation of bone marrow myeloblasts in AML.
