Recent letters
Displaying 1-10 letters out of 261 published
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Re:Pharmacokinetics of recombinant factor VIII Fc fusion protein
Submit responseTo the Editor:
We appreciate the comments and questions raised by Dr. Sven Bjorkman on our analysis of rFVIIIFc PK from the Phase 1/2a study, which we would like to address in this letter.
The PK profiles of both Advate and rFVIIIFc in individual patients were fit simultaneously by a user-defined WinNonlin ASCII model, which also simultaneously estimated the endogenous FVIII baseline based on two assumptions: [1] The endogenous FVIII level remains constant during the study period in each individual, and [2] the FVIII activity has returned to the endogenous baseline after the PK sampling schedule, that is more than five half-lives for both Advate and rFVIIIFc. The estimated baseline values were very close to the lowest observed values in all patients. For patients with lowest FVIII coagulation activity (FVIII:C) below the limit of quantification (0.5 IU/dL), the baseline estimate (mean ± SD) was 0.246 ± 0.224 IU/dL; for patients with lowest FVIII:C between 0.5 and 1 IU/dL, the baseline estimate was 0.556 ± 0.167 IU/dL.
We recognize that model-fitting for both Advate and rFVIIIFc is highly individualized, as indicated by the sensitivity analysis between one- and two-compartmental models using either the user-defined models or built-in WinNonlin library models (models 7 and 9). The 3-compartmental disposition model (model 19) was also tested; however, only one patient's Advate data can converge in this model. Hence the analysis focused on the comparison between one- and two-compartmental models.
Based on AIC criteria, the one-compartmental disposition (user-defined) model is a better fit for both Advate and rFVIIIFc in 10 out of 16 patients. For the remaining 6 patients in which the two-compartment disposition model was suggested to be a better fit by AIC, the primary PK parameter estimates are associated with exceedingly high %CV (150-500%) and condition numbers (5-3000 fold higher than one compartmental model) in 5 patients. In addition to AIC and %CV, we also visually inspected the curve fitting to ascertain the model appropriateness when models 7 and 9 were used to fit the baseline-corrected FVIII-activity-over-time profiles. In some cases, the two-compartmental model was not appropriate even with lower AIC and reasonable %CV, because the terminal phase included only one time point which is insufficient for accurate estimation. In brief, similar findings are observed in the comparative analysis using built-in WinNonlin library models 7 and 9, in which the Advate PK was better described by the one-compartment model in 9/16 patients, and the rFVIIIFc PK was better described by the one-compartment model in 11/16 patients.
More importantly, the PK results derived from one- or two-compartment models showed comparable quantitative extension in half-life and time to 1% for rFVIIIFc relative to Advate (Table 1). The half-life estimates for Advate using a user-defined two-compartmental model ranged from 11.2 hr to 23.7 hr with a mean (SD) of 17.3 hr (± 4.17), which is longer than that (11 and 12 hr) reported previously. (1,2). Similarly, the half-life of rFVIIIFc using the same two-compartment model was also substantially longer compared to our publication(3), ranging from 16.3 hr to 56.6 hr with a mean (SD) of 29.1 hr (±11.3), leading to similar prolongation (1.63 fold) in half-life compared to Advate. Time to 1% was also about 1.6-fold longer compared to Advate.
The difference in volume of distribution (Vss) between the dose groups is not resolved by two-compartmental model fitting (Table 1). Whether the difference in Vss resulted from the difference in the body weight distribution (89.5 kg in the 25 IU/kg group versus 78.7 kg in the 65 IU/kg group) remains to be determined.
In summary, recognizing the lack of a universally applicable model-fitting, and the comparable outcome between models, we have chosen a simpler one-compartment model which is adequate to describe the PK difference between rFVIIIFc and Advate in a limited number of patients in the Phase 1/2a study. The accuracy of the PK modeling and simulation will be further optimized and validated with PK data, including the periodic trough/peak measurements, from a much larger patient population in the Phase 3 study. In addition, population PK modeling will be used to resolve the ambiguity in selecting the conventional PK analysis methodologies and to better characterize the PK properties of rFVIIIFc.
Lian Li1, Jerry S Powell2, Neil C Josephson3, Doris Quon4, Margaret V Ragni5, Gregory Cheng6, Ella Li7, Jennifer A Dumont1, Jaya Goyal7, Xin Zhang1, Jurg Sommer1, Justin McCue7, Alvin Luk1, Glenn F Pierce1, Haiyan Jiang1
Affiliations
1Biogen Idec MA Inc, Weston, MA; 2University of California Davis, Sacramento, CA; 3Puget Sound Blood Center, Seattle, WA; 4Orthopedic Hospital of Los Angeles, Los Angeles, CA; 5University of Pittsburgh, Pittsburgh, PA; 6Prince of Wales Hospital, Shatin, Hong Kong; 7Biogen Idec MA Inc, Cambridge, MA
Table 1. PK parameters of Advate and rFVIIIFc by user-defined two-compartmental disposition model
Dose: 25 IU/kg Dose: 65 IU/kg Parameters Advate Geom. Mean
[95% CI]rFVIIIFc Geom. Mean
[95% CI]Geom. Mean Ratio
[95% CI]Advate Geom. Mean
[95% CI]rFVIIIFc Geom. Mean
[95% CI]Geom. Mean Ratio
[95% CI]t1/2β 14.6
[11.0, 19.2]23.7
[15.6, 36.0]1.62
[1.32, 2.00]18.5
[15.7, 21.8]30.1
[23.9, 37.7]1.63
[1.18, 2.24]Vss (mL/kg) 49.5
[43.9, 55.9]51.0
[44.0, 59.1]1.03
[0.904, 1.17]68.5
[56.7, 82.9]71.4
[61.0, 83.5]1.04
[0.880, 1.23]Time to 1% (day) 3.09
[2.35, 4.07]4.79
[3.67, 6.26]1.55
[1.38, 1.74]3.48
[2.86, 4.24]5.61
[4.21, 7.47]1.61
[1.42, 1.82]References
1. Bjorkman, S et al., Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight. Blood. 2012; 119(2): 612-618.2. Tarantino, MD et al., Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia. 2004 Sep;10(5):428-37.3. Powell JS et al., Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood. 2012 Mar 29;119(13):3031-7.Conflict of Interest:
Lian Li, Ella Li, Jennifer A Dumont, Jaya Goyal, Xin Zhang, Jurg Sommer, Justin McCue, Alvin Luk, Glenn F. Pierce, and Haiyan Jiang are all employees of Biogen Idec.
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Response to To SWiTCH or not to SWiTCH
Submit responseThe authors should be congratulated on the successful and timely recruitment of patients to a clinical trial in Sickle Cell Disease. However, as is the case for most Sickle Cell research, this was a pediatric study population (mean age 13 years), and there remains a paucity of data to guide adult Hematologists caring for patients who have suffered a distant stroke in childhood. The plasticity of pediatric neuronal connections, along with differences in prevalence, with age, of ischemic and hemorrhagic stroke, puts into question the applicability of extrapolating pediatric outcomes and observations to adult patients.
The definition of maximum tolerated dose in this study was conservative, more so than other trials involving Hydroxyurea, and one wonders whether greater benefit would have been gained by further dose escalation, although acknowledging the mean HbF level reached almost 20%.
For Hemoglobinopathy programs that follow a protocol of partial manual exchange transfusion, the iron overload burden is a minor consideration in the patient's overall care, and often permits relatively low dosing of iron chelation therapy. Many patients wish to reduce their risk of recurrent stroke at all cost, and continue with chronic transfusions. In addition, there is little long-term data on the morbidity associated with hepatic iron overload in Sickle Cell Disease, and therefore remains little incentive for patients to abandon effective treatment in the form of transfusions.
The future may herald the use of a combination approach with Hydroxyurea and transfusion, the former modifying the non-RBC factors implicated in vaso-occlusion and vasculopathy. This is particularly relevant for patients who have had a recurrent neurological event despite optimal HbS suppression. If inflammatory and endothelial biomarkers were collected as part of this protocol, this information may assist in the development of future clinical trials in adults and children with Sickle Cell and stroke.
Conflict of Interest:
None declared
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Which trials with anticoagulants do children with stroke actually need?
Submit responseAs clinicians involved in the care of children with stroke, we were interested in the paper establishing safety of anticoagulants in arterial ischemic stroke (AIS).[1] Nevertheless, we do not fully concur that the results support therapeutic trials with anticoagulants. Safety alone does not justify a placebo-controlled trial when observational data suggest that aspirin reduces recurrence and unfavourable functional outcome following childhood AIS vs. natural history.[2-4] Furthermore, aspirin appears to be as effective as anticoagulants in terms of recurrence,[5] and is cheaper and less burdensome.
Most pediatric AIS are due to non-progressive unilateral and proximal intracranial arteriopathies occurring in healthy children, often presenting with deep infarcts. Patients with basal ganglia infarction were more likely to be anticoagulated in Schechter's study, and a substantial proportion probably had proximal arteriopathy. In this population, the rate of recurrence is notably lower than the 16-50% cited by Schechter et al.[5] Of 74 European children with non-progressive anterior circulation intracranial arteriopathy, 91% received antithrombotic treatment at any time, 78% with aspirin alone.[3] A reanalysis of the original data showed that of the ten children who had a new stroke, only four recurred on aspirin. Of 72 additional French children with cryptogenic AIS (including focal arteriopathy), 85% were treated with long term aspirin alone. Five (7%) had a recurrence after a mean follow-up of 27 months, and only one of 54 with anterior stroke (personal data).
As many child neurologists are using aspirin in AIS, stroke recurrence rate is now low, except in some specific circumstances such as moyamoya, where revascularisation may be a better option than antithrombotics. It is thus uncertain that a trial comparing anticoagulants vs. aspirin in the general setting of childhood AIS will be justified. It will probably be more relevant to focus on specific populations, e.g. children suffering from longstanding prothrombotic conditions, extracranial dissection, or posterior AIS.
1. Schechter T, Kirton A, Laughlin S, et al. Safety of anticoagulants in children with arterial ischemic stroke. Blood 2012;119:949-56.
2. Ganesan V, Prengler M, Wade A, Kirkham FJ. Clinical and radiological recurrence after childhood arterial ischemic stroke. Circulation. 2006;14;114:2170-7.
3. Braun KP, Bulder MM, Chabrier S, Kirkham FJ, Uiterwaal CS, Tardieu M, Sebire G. The course and outcome of unilateral intracranial arteriopathy in 79 children with ischaemic stroke. Brain 2009;132:544-57.
4. Chabrier S, Husson B, Lasjaunias P, Landrieu P, Tardieu M. Stroke in childhood: outcome and recurrence risk by mechanism in 59 patients. J Child Neurol. 2000;15:290-4.
5. Strater R, Kurnik K, Heller C, Schobess R, Luigs P, Nowak-Goettl U. Aspirin versus low-dose low-molecular-weight heparin: antithrombotic therapy in pediatric ischemic stroke patients: a prospective follow-up study. Stroke 2001;32: 2554-58.
Conflict of Interest:
None declared
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Chronic GVHD plays a major role for survival and relapse after allogeneic hematopoietic stem cell transplantation for myelofibrosis
Submit responseRecently, Scott and co-workers reported on the predictive value of the dynamic international prognostic scoring system (DIPSS) for myelofibrosis considering the outcome after allogeneic hematopoietic stem cell transplantation (HSCT) (1). They presented an evaluation of 170 patients transplanted for myelofibrosis and could demonstrate by an excellent statistical analysis that DIPSS classification was associated with several endpoints for outcome after HSCT. Furthermore, the superior median survival post HSCT for all risk groups compared to the median life expectancy without HSCT could be elaborated. Finally, due to the large patient cohort Scott et al. succeeded in showing the significance of pre- HSCT splenectomy on post-transplant mortality.
Our findings in 76 myelofibrosis patients who underwent allogeneic HSCT are comparable to the reported results of Scott et al. and confirm the ability of DIPSS classification to significantly discriminate predicted post-transplant survival referring to the corresponding risk groups (2). We could show that application of the DIPSS plus score (3) might contribute to an even more accurate discrimination of post- transplant survival. However, in 67 patients surviving longer than 100 days after HSCT the development of chronic graft-versus-host-disease (GvHD) could be identified as a strong independent risk factor for improved overall and relapse-free survival and diminished relapse risk (2). Chronic GvHD incidences were 62%, 60%, 64% and 50% among DIPSS low, intermediate-1, intermediate-2 and high-risk patients. We found both predicted overall and relapse-free survival to be significantly lower in patients receiving HLA-mismatch transplantations. While Scott et al. noted an unexplained trend toward increased mortality among patients with secondary myelofibrosis we indeed found inferior overall survival in this patient subset.
So disease-specific factors as DIPSS scores do predict outcomes after HSCT but additionally there are transplant-specific features that independently determine outcome as well.
References
1. Scott BL, Gooley TA, Sorror ML, Rezvani AR, Linenberger ML, Grim J, et al. The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation. Blood. 2012;119(11):2657-64. Epub 2012 Jan 10.
2. Ditschkowski M, Elmaagacli AH, Trenschel R, Gromke T, Steckel NK, Koldehoff M, et al. DIPSS scores, pre-transplant therapy and chronic GVHD determine outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis. Haematologica. 2012 Apr 4. [Epub ahead of print]
3. Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29(4):392-7. Epub 2010 Dec 13.
Conflict of Interest:
None declared
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Suspending CART in HIV-associated lymphoma
Submit responseWe thank Goptal and colleagues for their response to our 'how I treat' paper and their comments on the use of concurrent CART during chemotherapy in HIV-associated lymphoma. While we realize that newer antiretroviral drugs may have fewer drug interactions (compared to older agents) with chemotherapy agents, we remain cautious about advocating the use of concomitant CART at this time1-3. In addition to pharmacokinetic and pharmacodynamic interactions, the possible inhibitory effects of CART on lymphocyte apoptosis are also of potential concern4. Importantly, we have demonstrated that structured CART suspension does not increase infectious events in these patients and in our studies with EPOCH and EPOCH-R, the lymphoma-free survival is excellent. Effective options for patients with relapsed HIV-associated lymphoma are extremely limited and strategies that could possibly compromise therapeutic efficacy in newly diagnosed patients, should be avoided, we believe. Having said that, we appreciate that this is a controversial question that has not been well or rigorously studied and should be investigated in future prospective studies, particularly in severely immunocompromised patients.
1. Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood. Jun 15 2003;101(12):4653-4659.
2. Dunleavy K, Little RF, Pittaluga S, et al. The role of tumor histogenesis, FDG-PET, and short-course EPOCH with dose-dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse large B-cell lymphoma. Blood. Apr 15 2010;115(15):3017-3024.
3. Dunleavy K, Wilson WH. How I treat HIV-associated lymphoma. Blood. Apr 5 2012;119(14):3245-3255.
4. Mounier N, Katlama C, Costagliola D, Chichmanian RM, Spano JP. Drug interactions between antineoplastic and antiretroviral therapies: Implications and management for clinical practice. Crit Rev Oncol Hematol. Oct 2009;72(1):10-20.
Conflict of Interest:
None declared
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Purely obstetric antiphospholipid syndrome (APS): antithrombotic treatment outside the pregnancy period?
Submit responseWe read with interest the paper by Gris et al. on "Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study" [1]. In this observational study, purely obstetric antiphospholipid syndrome (APS) had significantly more thromboembolic events than control groups despite low-dose aspirin primary prophylaxis. Unfortunately, no treatment implication can be drawn from this study as we do not know if aspirin works and should be given to all these patients. In two multicenter studies we observed that purely obstetric APS was not an independent risk factor for a first thrombotic event [2, 3]. Moreover, the low annualized incidence rate of events in the study of Gris et al. and in our studies (1.48%/y in the retrospective and 2.11%/y in the prospective studies, respectively) is against an antithrombotic treatment to all the patients with purely obstetric APS. Therefore, identification of patients' subgroup at risk would be important. The laboratory profile and associated risk factors for thrombosis are main issues to be considered. Triple antiphospholipid antibody positivity (positive lupus anticoagulant and positive anticardiolipin/anti-?2 Glycoprotein I antibodies, same isotype) is indeed a strong risk factor for a first thromboembolic event in otherwise healthy subjects [4] and is a significant predictor in the cohort described by Gris et al (see Table S1). In addition, most (10 out of 12) of the purely obstetric APS with an incident thrombotic event during the follow-up in the above mentioned studies [2,3] had other important risk factors for thrombosis. In conclusion we think that an antithrombotic treatment should be considered for selected purely obstetric APS patients with a high risk antibody profile and/or those with other relevant risk factors for thrombosis.
References
1. Gris JC, Bouvier S, Molinari N et al. Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study. Blood. 2012;119(11):2624-2632.
2. Ruffatti A, Del Ross T, Ciprian M et al. Risk factors for a first thrombotic event in antiphospholipid antibody carriers. A multicentre, retrospective follow-up study. Ann Rheum Dis. 2009;68(3):397-399.
3. Ruffatti A, Del Ross T, Ciprian M et al. Risk factors for a first thrombotic event in antiphospholipid antibody carriers: a prospective multicentre follow-up study. Ann Rheum Dis. 2011;70(6):1083-1086.
4. Pengo V, Ruffatti A, Legnani C et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood. 2011;118(17):4714-4718.
Conflict of Interest:
None declared
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Chemoimmunotherapy with Rituximab and low-dose oral fludarabine and cyclophosphamide (R-FC-low dose os) as initial treatment for elderly patients with chronic lymphocytic leukemia
Submit responseWe read with great interest the paper by Foon et al.,1 in which they report about long term results of FCR Lite in CLL. We would like to add few comments since we gained quite experience in using low dose fludarabine and cyclophosphamide (FC), as intravenous but even most as oral administration (os= latin translation for orally) in elderly patients with chronic lymphoproliferative disorders (CLDs). The authors did not mention this alternative route of administration that could represent instead a good option in CLL management especially since median age at diagnosis is now 72 years.We previously showed that FC given intravenously at low doses in relapsed or refractory indolent lymphoid malignancies can decrease the incidence of infectious complications.2 Then we demonstrated that low-dose oral fludarabine and cyclophosphamide (FC-low dose-os) given to pretreated elderly patients with CLDs enabled response rates that were comparable to those obtained with standard i.v. regimens with few side effects and complications.3 These responses were confirmed in a population of untreated elderly low grade non Hodgkin lymphoma patients.4 Finally we showed that in 26 elderly CLL patients (14 untreated, 12 treated) who cannot benefit of more aggressive schedules, FC low-dose-os led to a median progression-free survival (PFS) of 48 months with 65% of CRs in the untreated population.5 The oral regimen was easily managed on an outpatient basis.
We recently added Rituximab to FC-low dose-os to treat 40 untreated elderly patients with CLDs (15 CLL, 25 NHL). Patient's characteristics were listed and compared with updated results of 57 patients with CLDs treated with FC. Median number of cycles of R-FC low dose-os received was 4. Of note 100% of untreated CLL patients achieved a response (87% CR) and PFS was still not reached at median follow up of 35 months. Hematological toxicity was acceptable.
References
1) Foon KA, Mehta D, Lentzsch,et al. Long term results of chemoimmunotherapy with low dose fludarabine, cyclophosphamide and high dose rituximab as initial treatment for patients with chronic lymphocytic leukemia Blood 2012;119(13):3184
2) Bocchia M, Bigazzi C,Marconcini S, et al. Favorable impact of low dose fludarabine plus epirubicin and cyclophosphamide regimen (FLEC) as treatment of low grade non Hodgkin lymphoma Haematologica 1999; 84:716-720
3) Fabbri A, Lenoci M, Gozzetti A, et al.,Low dose oral fludarabine plus cyclophosphamide in elderly patients with chronic lymphoproliferative disorders The Hematology Journal 2004; 5:472-474
4) Fabbri A, Lenoci M, Gozzetti A, et al., Low dose fludarabine plus cyclophosphamide as first line treatment in elderly patients with indolent non-Hodgkin lymphoma British Journal of Haematology 2007; 139:90-93
5) Forconi F, Fabbri A, Lenoci M, et al., Low dose fludarabine plus cyclophosphamide in elderly patients with untreated and relapsed or refractory chronic lymphocytic leukemia Haematol Oncol 2008; 26: 247-251
Conflict of Interest:
None declared
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Screening strategy not likely to be cost-effective
Submit responseWe have read with great interest and appreciation the comment of Dr Bender on our research in which he provides a comprehensive overview of VWF and ADAMTS13 in clinical disease.[1,2] Additionally, he focuses on the synergistic effect of VWF / ADAMTS13 levels and oral contraceptive (OC) use and raises the question whether women starting OC would benefit from screening strategies based on these plasma markers.
We would argue that such a screening strategy is not likely to be cost-effective. We performed some calculations using population statistics and the combination of high VWF and OC use which yielded the highest increase in risk. With an annual incidence of myocardial infarction of 14 per 100 000 women aged 18-50 per year[3], 2739 women with high VWF levels should refrain from starting OC use annually in order to prevent one case of myocardial infarction. However, since 'high VWF' in our study was defined as >90th percentile of the general population, we would need to screen ten times as many women, i.e. 27 385. Similarly, 14 298 women need to be screened to prevent one case of ischemic stroke annually.[4]
Although this is not a formal cost-effectiveness analysis, these numbers indicate that such a screening program is not warranted. The main reason for this, perhaps counterintuitive result given the high relative risks, is that for young women the incidence of myocardial infarction and ischemic stroke, or any other disease for that matter, is very low. Therefore, it is not likely that any genetic or plasma marker based screening program used to determine which women could 'safely' start using OC would ever be cost effective.[5,6]
These interaction analyses are, however, still important: they raise questions on the causal mechanisms underlying this additional risk, as is also done succinctly by Dr Bender in his comment.
Bob Siegerink, Helena M Andersson, Brenda M Luken, James TB Crawley, Ale Algra, David A Lane and Frits R Rosendaal
References
1.Bender M. High VWF, low ADAMTS13 puts women at risk. Blood. 2012;119(6):1329-30.
2. Andersson H, Siegerink B, Luken B, et al. High VWF, low ADAMTS13, and oral contraceptives increase the risk of ischemic stroke and myocardial infarction in young women. Blood. 2012;119(6):1555-1560.
3. The Dutch Heart Foundation. Cardiovascular disease in the Netherlands. Chapter 3: incidence of myocardial infarction. 2004.
4. The Dutch Heart Foundation. Cardiovascular disease in the Netherlands. Chapter 3: incidence of ischaemic stroke. 2006.
5. Vandenbroucke JP, van der Meer FJM, Helmerhorst FM, Rosendaal FR. Factor V Leiden: should we screen oral contraceptive users and pregnant women? British Medical Journal. 1996;313(7065):1127-1130.
6. Rosendaal FR. Oral contraceptives and screening for factor V Leiden. Thrombosis and haemostasis. 1996;75(3):524-5.
Conflict of Interest:
None declared
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Tissue factor and hematological neoplasias
Submit responseThe recent review by Van den Berg et al. discusses the well- recognized correlation between cancer and aberrant hemostasis,as well as the expression of tissue factor (TF) by neoplasiasas a link between thrombosis and aggressive tumor behavior[1]. Indeed, venous thromboembolism (VTE) in individuals with solid tumors has been associated with a poor prognosis[2]. TF, which triggers coagulation, is expressed in a variety of solid tumors. Genetic abnormalities affecting oncogenes and tumor suppressor genes directly enhance TF expression[3]. The mechanisms of thrombosis in hematological malignancies may differ from solid tumors. For instance,VTE does not impact survival despite the high prevalence of thrombosis in multiple myeloma (MM), particularly those receiving treatment with oral immunomodulatory drugs concomitantly with dexamethasone[4]. We recently described the absence of TF gene (F3) expression by microarray analysis in all 58 MM cell lines and 239 patient samples[5]. This finding suggests that activation of coagulation and malignant behavior in MM are not driven by TF on neoplastic plasma cells. To determine the relevance of TF in other hematological neoplasias we analyzed F3 expression levels on a variety of cell lines established from lymphoid and myeloid neoplasias available at GlaxoSmithKline (GSK) Cancer Cell Line Genomic Profiling Dataset (https://array.nci.nih.gov/caarray/project/woost-00041). The presence/absence of gene expression was calculated using MAS5 transformation algorithm. Interestingly, F3 was absent in all lymphoid and in most of myeloid cell lines (only expressed in 25%), in sharp contrast to the common expression (~73%) in a wide variety of cell lines originated from solid tumors. We propose that the TF produced by the neoplastic cells themselves might drive malignant behavior, though TF derived from non-neoplastic cell sources may still be relevant for the development of thrombosis. Thus, treatment directed against tumor-associated TF as proposed by Van den Berg et al. would not be expected to be useful in hematological neoplasias.
Conflict of Interest:
We have no conflict of interest to declare
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Role of P.jiroveci prophylaxis and risk for drug resistance development
Submit responseA propos of the excellent and exhaustive review on HIV- related lymphomas and the ensuing treatment recommendations by Dunleavy and Wilson ( 1 ), we would like to remark about two items. First, we usually begin cotrimoxazole prophylaxis together with chemotherapy even with high levels of CD4 cell counts. The addictive immune suppressant effects of HIV infection, lymphoma per se and chemotherapy warrant an early institution of a prophylaxis (2) which otherwise would be initiated at a cut-off of 200 CD4 lymphocyte (3), not 100 as suggested in Dunleavy's and Wilson's paper. And much more so as CART withdrawal, advocated by the authors, puts patients at increased risks of developing opportunistic infections. Second, the apparent reversion of HIV to a wild-type phenotype after CART withdrawal is a well known virologic event, but it has no positive implication for further therapeutic choices. Actually, pre-existing mutations never really disappear but remain frozen in a subset of quiescent archive cells, ready to reappear with therapy reinstatement (4,5). So, we don't think that it should be regarded as a positive consequence of, or as confirmation of the indication to, therapy suspension .
1. Dunleavy K, Wilson WH. How I treat HIV associated lymphoma. Blood. 2012;119(14):3245-3255
2. Green H, Paul M, Vidal L, et al. Prophylaxis of pneumocystis pneumonia in immunocompromised non -HIV- infected patients: systematic review and meta analysis of randomized controlled trials. Mayo Clin Proc 2007; 82:1052-1059
3. Stansell JD, Osmond DH, Charlebois E at al. Predictors of pneumocystis carinii pneumonia in HIV infected persons. Pulmonary Complications of HIV Infection study Group. Am J Respir Crit Care Med 1997; 155:60-66
4. Palmisano L, Giuliano M, Bucciardini R, et al. Determinants of virologic and immunologic outcomes in chronically HIV -infected subjects undergoing repeated treatments interruptions: the Istituto Superiore di Sanit?-Pulsed Antiretroviral therapy (ISS-PART) study. J Acquir Immune Defic Syndro 2007;46(1):39-47
5. Scweighardt B., Ortiz GM, Grant RM, et al. Emergence of drug resistant variants in patients undergoing structured treatment interruptions. AIDS 2002;16(17):2342-2344
Conflict of Interest:
None declared
