Elderly patients with advanced chronic lymphocytic leukaemia (CLL) and functional impairment pose a significant therapeutic challenge for developing treatment modalities that are curative or at least prolong and improve the quality of life (Shanafelt, 2013). Such patients are also rarely candidates for clinical trials and are thus deprived of hope for curative treatment. Furthermore, even when novel treatment approaches are proven effective, they are rarely used in such frail patients, because of the fear of possible complications, which are very different from those of the trial populations (Niraula et al, 2012). We have previously established the role of CD74 in the survival and homing of CLL cells in vitro and showed that blocking of CD74 using the monoclonal antibody milatuzumab leads to a significantly decreased survival of CLL cells in vitro and to decreased migration of these cells to the bone marrow in a xenograft model (Binsky et al, 2007; Shachar & Haran, 2011). At that time a phase I clinical trial with milatuzumab in patients with advanced stage multiple myeloma showed a favourable side effect profile of this agent (Kaufman et al, 2013). The feasibility and benefit of an approach combining comfort care with investigational therapy was demonstrated in one small study (Meyers et al, 2004). We therefore decided to take a less traditional approach and design a unique patient-centred phase I–II clinical protocol of milatuzumab combined with comfort care in elderly patients with refractory CLL, who were not eligible for any other form of treatment due to decreased performance status, recurrent and severe infections, other comorbidities or significant cytopenias (see supporting material for details). After obtaining informed consent, 8 patients with advanced refractory CLL satisfying International Workshop on CLL (iwCLL) criteria (Hallek et al 2008), were enrolled in two participating centres. The average age was 75 (range: 65–81) years, with an average of 3 prior lines of treatment (range: 2–6). All patients had recurrent infections including severe pneumonia with resistant organisms. Most had significant cytopenias and/or multiple comorbidities. The average Eastern Cooperative Oncology Group (ECOG) performance score (PS) was 2·5 (range: 1–4) and the quality of life (QOL) score was 6 (range: 3–8/max of 10). Three patients were wheelchair bound and two required a cane to aid walking. The best response to milatuzumab was seen in one patient, whose disease progressed on treatment with FCR (fludarabine/cyclophosphamide/rituximab), and had an ongoing response for more than 18 months, nearly satisfying iwCLL criteria for partial response (Hallek, et al 2008). Two other patients who required packed red cell transfusions prior to treatment had a gradual decrease in their need within a few weeks as a well as a significant increase in platelet counts (Fig 1). Of the 6 patients who had enlarged spleens, 3 showed a decrease in spleen size ranging from 3 to 9 cm. There was also a marked improvement in the average QOL (from 6 to 8) and in 4 patients there was also improvement in the ECOG PS. Three patients had an improvement that enabled them to restart chemotherapeutic treatment. (See Table 1 for details, supplementary material for representative case descriptions). CHF, AF Recurrent respiratory infections FCR ×3 lines APSCT Able to walk with difficulty ECOG PS 2 Fully ambulatory ECOG PS 1 LP FCR ×2 lines Able to walk at a slow pace ECOG PS 1 Marked Improvement in feeling of well being ECOG PS 1 Severe Cachexia Recurrent infections 17p del. LP Progression On FCR Wheelchair bound ECOG PS 4 Fully ambulatory; able to cook for her entire family ECOG PS 0 Inoperable hernia 17p del. Recurrent respiratory infections LP alemtuzumab ×2 lines Wheelchair bound ECOG PS 4 Able to walk with cane ECOG PS 2 COPD Recurrent respiratory infections FCR alemtuzumab Able to walk at a slow pace ECOG PS 1 No change ECOG PS 1 IHD Pulmonary HTN Orthopedic injury with chronic osteomyelitis Recurrent infections LP FCR ciclosporin Wheelchair bound ECOG PS 4 No change ECOG PS 4 CRF Recurrent respiratory infections With resistant organisms FCR ×3 lines APSCT Able to walk with cane ECOG PS 3 Able to walk without cane ECOG PS 2 Mild asthma Recurrent respiratory infections Orthopedic injury Able to walk with walker ECOG PS 2 No change ECOG PS 2 Interestingly, those patients who had a response showed a significant increase in lymphocyte counts following each infusion of milatuzumab. In fact, a statistically significant correlation (P < 0·001) was found between WBC count increase following treatment and increase in platelet count and haemoglobin level. This calculation was done on all infusions (a total of 188). Treatment with milatuzumab led to a decrease in the levels of the antiapoptotic protein BCL2 in peripheral blood CLL cells, as previously reported in detail (Binsky-Ehrenreich et al, 2014). However, we did not see a uniform change in the expression of VLA-4 and cell adhesion, nor was there a clear pattern in the serum levels of cytokines (IL8, IL6, IFN-γ, MIP1β, IL10, MIP1α), before and after treatment with milatuzumab. The most common significant adverse event was infection requiring hospitalization. Overall there were 8 episodes, one of which was fatal in a patient with recurrent pneumonia due to resistant organisms (which occurred 2 months beyond the planned study period). None of these episodes was deemed related to the study medication. In fact, patients who responded to treatment showed a trend towards a decrease in the frequency and severity of infections, with a decrease in days of hospitalization. Two patients had grade 1–2 transient transfusion reactions that did not require discontinuation of the study medication. One patient had a mild, transient thrombocytopenia. There was no change in serum chemistries, liver or renal function tests. There was also no effect on immunoglobulin levels. In contrast to another study of milatuzumab (Martin et al, 2015), transient neutropenia did not occur in our cohort. In this unique patient-centred study, a modest response in haematological parameters and a meaningful improvement in QOL and/or performance/functional status was observed in most patients, suggesting that this was an effective and feasible approach. The mode of action of milatuzumab seemed to be similar to that observed in vitro and in a xenograft mouse model (Shachar & Haran, 2011). There was similar direct evidence for an effect of milatuzumab on apoptosis, as evidenced by a reduction of the levels of the antiapoptotic protein BCL2. However, we did not see a clear effect of treatment on VLA-4 expression and cell adhesion. This is probably due to the fact that milatuzumab leads to mobilization of cells from the bone marrow and spleen as well as to increased apoptosis. This creates a dynamic modulation in the population of lymphocytes in the peripheral blood, in which freshly mobilized cells differ from cells on the verge of apoptosis in their VLA-4 expression and adhesion properties. A "snapshot" view may not adequately reflect this dynamic biological process. The statistically-significant correlation between the rise in lymphocyte counts and increased platelet counts and haemoglobin levels suggests that mobilization of cells from the bone marrow is a significant part of the mechanism. This phenomenon is now widely recognized in other medications, such as ibrutinib (Herman et al, 2014). A limitation of this study was the small number of patients and the difficulty in assessing efficacy/optimal effective dose in this heavily pre-treated ill population. Interestingly, traditional poor prognostic factors, such as 17p del did not seem to play a role in the response to milatuzumab therapy. Further studies are required to assess the utility of this agent in the treatment of CLL, possibly in combination with other agents. Haran designed the research, performed the research, analysed the data and wrote the paper. Mirkin performed the research, analysed the data and wrote the paper. Braester performed the research, Harpaz performed the research, Shvetz performed the research and wrote the paper, Shtreiter designed and performed the research, Greenberg, Amram, Mordich, Binsky, Marom performed the research, Ruchlemer and Herishanu provided essential reagents and tools, Shachar performed the research and wrote the paper, Valinsky analysed the data, Shtalrid (deceased) designed and performed the research, Shvidel designed the research and wrote the paper. The authors would like to thank the Israeli CLL study group for participation and support, Dr. David Goldenberg and Imunomedics for kindly providing the study medication. This study was funded by a grant from the Israel Cancer Association. Fig S1. Schematic representation of the dual role of CD74 activation by MIF ) macrophage inhibitory factor). CD74 has a direct effect on CLL survival by elevating bcl-2, and an indirect effect by increasing the expression of VLA-4. (From Shachar & Haran, 2011). Fig S2. Study protocol .After a rapid increment from 30 mg/m2 (cohort I)/60 mg/m2 (cohort II), milatuzumab was given twice weekly for 12 weeks at a dose of 120 mg/m2 (cohort I)/240 mg/m2 (cohort II). After a washout period of 4 weeks, treatment was resumed at escalating doses up to 480 mg/m2 (cohort I)/600 mg/m2 (cohort II). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Structural mitochondrial abnormalities as well as genetic aberrations in mitochondrial proteins have been known in Myelodysplastic syndrome (MDS) , yet there is currently little data regarding the metabolic properties and energy production of MDS cells. In the current study we used state-of-the-art methods to assess OXPHOS in peripheral blood cells obtained from MDS patients and healthy controls We then assessed the effect of food supplements- Coenzyme Q10 and carnitine on mitochondrial function and hematological response .We show here for the first time that in low risk MDS there is a significant impairment of mitochondrial respiration in peripheral blood cells and this can be improved with food supplements. We also show that such myelodysplastic syndrome, mitochondria, oxidative phosphorylation, coenzyme Q10, seahorse XF analyzer. supplements lead to improvement in cytopenia's and quality of life.
The current study evaluated the prognostic significance of the monoallelic deletion of the whole locus of the immunoglobulin heavy-chain (w_del(IGH)) gene compared to translocations t(4;14) and t(14;16) among newly diagnosed multiple myeloma (MM) patients. We retrospectively analyzed clinical (age, gender, and staging) and laboratory data at diagnosis and the overall survival (OS) of 255 newly diagnosed MM patients carrying w_del(IGH) or translocations t(4;14) or t(14;16). Bone marrow samples were examined by morphological and sequential interphase fluorescense in situ hybridization analyses. Among 255 patients, 117 (45.8%) had w_del(IGH), 99 (38.8%) had t(4;14), and 39 (15.3%) had t(14;16). Mean age was 61.6 ± 11.6 years. Groups did not differ significantly in age, gender, or lactate dehydrogenase levels. Patients in the w_del(IGH) group presented more frequently at International Staging System stage I than at stage II/III. Patients in the w_del(IGH) group had significantly fewer additional chromosomal aberrations (1.58) than the other two groups (2.3 and 2.13 in the del(IGH), t(14;16) and t(4;14) groups, respectively, P < 0.0001). Furthermore, the w_del(IGH) group had significantly longer estimated median OS (9.47 years) compared to those with translocations t(14;16) (3.02 years, P = 0.002) or t(4;14) (4.18 years, P = 0.001), respectively. These findings suggest a potential prognostic significance of monoallelic deletion of IGH among these patients. Additional studies are needed to better understand the nature and mechanism of this prognostic factor.
Summary Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma ( RR ‐ MM ). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR ‐ MM outside of a clinical trial setting was conducted by our group. One hundred and thirty‐five patients were included. All patients had been previously exposed to bortezomib and 93% had also been treated with lenalidomide. The vast majority of patients received carfilzomib as part of a two‐ or three‐drug combination. The overall response rate was 47·2%. Multivariate analysis revealed bortezomib resistance, lenalidomide resistance and albumin <35 g/l to negatively impact the likelihood of achieving response. The median duration of response was 8·4 months, and was significantly higher in patients receiving three‐drug combination and patients presenting without extramedullary disease. The median progression‐free survival and overall survival for the entire cohort was 4·9 months (95% confidence interval [ CI ] 3·8–6·4) and 12·2 months (95% CI 9‐not reached), respectively. Toxicity was manageable, although treatment‐related death was seen in 5% of patients. In the setting of progressive multiple myeloma, carfilzomib in a combination regimens yields effective results with a manageable toxicity.
Light-chain amyloidosis (AL) is associated with low survival rates, particularly in patients with cardiac involvement. We evaluated the outcome of 73 consecutive, non-selected 'real-world' AL patients, treated with first-line bortezomib-based induction, focusing on the benefit of concurrent administration of alkylating agents. Most patients had renal (77%), cardiac (66%), or multiorgan (74%) involvement. Sixty-eight per cent (n = 50) received alkylating agent (mostly cyclophosphamide). Severe adverse events were seen in 45%, most evident in patients with cardiac involvement, with no increased toxicity in patients receiving an alkylator agent. Hematological response (HemR) was obtained in 77% of patients, including 33% very good partial responses and 19% complete responses. Age <70 yr, lack of cardiac and peripheral neurologic involvement, and co-administration of an alkylating agent were associated with significantly improved HemR. NYHA cardiac failure staging was the only independent factor affecting overall survival. Administration of an alkylating agent and the achievement of both HemR and organ response were associated with a statistically significant improved survival in those surviving the first 6 months of induction. First-line bortezomib-based regimen resulted in favorable response and survival in newly diagnosed patients. Co-administration of an alkylating agent improved outcome without increasing treatment-related toxicity.
