Fast-gradient Microbore Column-Switching LC-MS/MS for the QuantitativeG. Hopfgartner, C. Husser, M. Zell, Department of Non-Clinical Drug Safety,F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, CH-4070 Basel, SwitzerlandProceedings 48th ASMS Conference on Mass Spectrometry and Allied Topics, Long Beach, CA, USA, 2000 Introduction The examination of pharmacokinetic properties of drugs in dis
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èktþÿ••EPOETIN ALPHA IN MULTIPLE MYELOMA-RELATED ANAEMIA High-doses epoetin alpha in patients with multiple myeloma- related anaemia: early response and effective maintenance Pasquale Niscola, Laura Scaramucci, Luigi Menichelli1, Velia Bongarzoni, Cinzia De Gregoris, Marco Morucci, Vincenzo Tini, Marco MontanaroHaematology Unit, 1Pharmacy Unit, Montefiascone Hospital, Viterbo, Italy Abstract. In this report we analyse the results of a pilot and open study on the management of the disease-related anaemia in patients with multiple myeloma, evaluating the efficacy and tolerability of a new regimen using high doses of erythropoietin-alpha (Epo-alpha, 40,000 IU) given twice weekly. Pa- tients who responded to initial treatment continued on maintenance treatment with Epo-alpha given at a longer dosing interval. Intravenous iron supplementation was given during the first four weeks of treat- ment and periodically, if required, during the maintenance phase. Transfusions were given according to clinical criteria. Overall, 9 out of 10 patients (90%) responded to treatment. Out of these, 8 achieved the correction of anaemia within the first four weeks of treatment, with a median response time of 2 weeks (range: 1-4 weeks), and one patient showed a late response, becoming transfusion independent after 7 weeks. This new dosing regimen achieved a rapid erythroid response in high percentage of patients and permitted to titrate treatment as necessary to maintain stable haemoglobin values.
Key words: anemia multiple myeloma erythropoietin epoetin alpha* Correspondence: Pasquale Niscola, MD, Azienda Sanitaria ASL Viterbo, Unitá Operativa di Ematologia, Ospedale di Montefiascone, Via Verentana 23, 01027 Montefiascone, Viterbo, Italy, Tel.:+390761.833232, Fax:+390761.833265, e-mail: [email protected] ished Epo production by the kidney2, the decreased responsiveness of erythroid progenitors to Epo3,4 and Anaemia is one of the most common clinical find- the impairment of iron metabolism5. Recently, eryth- ings in patients with multiple myeloma (MM). A num- roblasts cytotoxicity, promoted by highly malignant ber of mechanisms may contribute to its development: myeloma cells which over-express Fas-ligand and myelosuppressive effect of chemotherapy, anaemia of TRAIL receptors, has been considered as another crit- chronic disease, including a decreased erythrocyte ical event in the pathogenesis of anaemia in MM pa- survival, a relative erythropoietin (Epo) deficiency and tient with advanced and progressive disease6. Several a diminished marrow response to erythropoietin due trials have demonstrated that recombinant human Epo to the presence of inflammatory cytokines1. Addition- (epoetin) can significantly reduce transfusion require- ally, such cytokines (tumor necrosis factor-alpha and ments and improve the patients quality of life7-10.
interleukines 1 and 6) may contribute to the dimin- The current recommended initial dose of epoetin in MM anaemic patients is 150 U/Kg subcutaneously males and 5 females with a median age of 72 (45-87) (SC)3 times a week11. This dose can be doubled if an years. Nine patients were in IIIA and one in IIA dis- adequate response does not occur after 4 weeks of thera- ease stage. Median time from diagnosis to initiation py12. In patients with B-chronic lymphoproliferative of epoetin-á was 38 months (range: 1-74 months). The disorders-related anaemia responding to epoetin treat- median number of the previous lines of anti-myeloma ment, the need of long-term maintenance treatment treatments was 2 (range: 0-5). Five patients, of whom to sustain the response has been demonstrated13. Re- 2 were transfusion-dependent, had relapsing or refrac- cent data from a trial involving a large number of pa- tory disease and received a concomitant treatment with tients with cancer-associated anaemia, has established thalidomide plus dexamethasone (Table 1). One of that the administration of 40,000 IU of epoetin, SC, these, presenting a 90% malignant plasma cells asso- once weekly was well tolerated and was as effective as ciated with some abnormalities of residual erythroid the standard three times weekly regimen14.
precursors, such as multinuclearity, karyorrhexis, in- So far, the potential role of high-dose (HD) epoet- ternuclear bridges, cytoplasmic vacuolation and in- in in the treatment of the MM associated- anaemia creased iron in the macrophages but no evidence of has not been extensively investigated. We carried out blasts on the bone marrow (BM) smears, entered also a pilot study to evaluate the efficacy and tolerability of a into the trial after the detection of no karyotypic ab- new dosing regimen with HD epoetin-alpha (epoetin-á) normality by conventional cytogenetic analysis. Al- for the management of MM-related anaemia.
though a secondary myelodysplastic syndrome, proba- bly related to the heavy previous alkylating therapies, was suspected on morphological basis we believed that in the development of the severe anaemia the major The aim of this study was to evaluate the efficacy of role was due to the MM progression and that the oth- HD epoetin-á administered twice weekly in correct- ers abnormality detected on the BM were responsible ing anaemia in patients with MM, as well as to evalu- for only a minimal contribution. Two patients were at ate the effectiveness of a maintenance treatment with the onset of disease: the first was on melphalan plus epoetin-á given at a longer dosing interval. Patients prednisone and the second on a multi-chemotherapy with MM-related anaemia, presenting an haemoglo- regimen prior to a planned allogeneic bone marrow bin (Hb) concentration less than 10g/dl, were enrolled transplantation (BMT). Three patients were in pla- in this non comparative pilot study. Patients with teau phase and were treated with a single monthly anaemia that could be related to other diagnosed caus- infusion of pamidronate (90 mg) or zolendronate (4 es of anaemia were excluded. Table 1 shows the pa- mg) associated with dexamethasone (40 mg). The tients clinical features. Diagnosis of MM was estab- mean (±SD) baseline Hb value was 8.5±0.7 g/dl. The lished according to the Durie and Salmon staging sys- median performance status score was 1 (0-3). The mean tem 15. A total of 10 patients entered in the study: 5 (±SD) serum erythropoietin level, measured in six EPOETIN ALPHA IN MULTIPLE MYELOMA-RELATED ANAEMIA patients, was 43±17 mU/ml. All patients received IV and one showed a late response, becoming transfusion iron supplementation during epoetin-á therapy, al- independent after 7 weeks. The median response time though serum ferritin values were normal or elevated.
was of 2 weeks (1-7). The patient with the associated All patients were properly informed and gave their erythrodysplasia was unresponsive to epoetin-á and the treatment was withdrawn at the 8th week. Out of Study design: epoetin-á 40,000 U, was given twice the 9 responders, 3 stopped the treatment after 10, 18, weekly (TW), SC, for 4 weeks or shorter period if Hb 26 weeks respectively; the first died because of an un- level was ³12 gr/dl. Unresponsive patients continued related MM illness, the second is well after an alloge- to receive the same treatment for up to 8 weeks. In neic BMT and, to date, presents normal Hb values patients presenting an Hb value higher than 14.0 gr/dl and no need for anti-anaemic treatment; the third died epoetin-á has to be withdrawn. After the induction because of a massive skeletal and pulmonary MM in- phase, based on the maintained response to epoetin-á, volvement. One patient, who had a very aggressive evaluated every two weeks, the dosing interval was pro- MM progression after a partial remission of MM dis- gressively longed. The responders received epoetin-á ease achieved by the combination of thalidomide plus 40,000 U once weekly (OW) for two weeks and then, if dexametasone, lacked the response requiring red maintaining an Hb level above 12.0 gr/dl, the same blood cells (RBC) transfusions after 52 weeks of treat- dose was given every two weeks while the other re- sponders with an Hb concentration lower than 12.0 gr/ To date, five patients have a sustained response at dl continued to receive a weekly dose. In patients pre- a median time of 24 weeks (range: 18-42 weeks). Out senting an Hb value higher than 13.0 gr/dl the dosing of these, two patients presented progressive and ad- interval was prolonged to three weeks. The previous vanced disease phase; the first is receiving OW dosage dosing interval was restarted in patients presenting a of epoetin-á, the second is on TW dose regimen, be- drop in the Hb value more than 1 gr/dl. Intravenous cause a drop in Hb value to <9 gr/dl was observed (IV) iron supplementation (gluconate iron, 125 mg/ after 2 months of successful treatment with the weekly week) was given by very slow infusion during the first dosage. This patient recovered to the previous Hb level four weeks of treatment, with the aim of avoiding the after restarting the TW schedule, avoiding transfusion.
functional iron deficiency and optimising the response Patients, who were in plateau phase of the disease, to epoetin-á. The same iron IV supplementation was are being treated with 40.000 U epoetin-á adminis- administered to responding patients in maintenance tered every two weeks from the 26th, 20th and 10th therapy only if hypochromic erythrocytes were >10% week respectively. Longer time interval (three weeks) of the total or transferrin saturation <20%. Transfu- between administration period was ineffective to main- sions were given according to clinical criteria, usually tain a steady Hb value in these three patients. No pa- when the haemoglobin concentration was less than 8 tients presented an Hb values higher than 14.0 gr/dl.
gr/dl or in case of organ-related symptoms referred to The HD epoetin-á and the IV iron supplementation anaemia. Major response was defined as an increase were well tolerated and no adverse events occurred.
of the Hb level by ³2 gr/dl and complete absence of blood transfusion requirements; minor response was defined as an increase of the Hb level by ³1 gr/dl and complete absence of blood transfusion requirements.
In the past, RBC transfusion was the only treat- ment option for the management of anaemia in pa- tients suffering from MM, inducing a rapid rise in Hb level. However, the gain in Hb level is modest and The response to HD of epoetin-á and the patients transient, and Hb values return to baseline within a clinical course are summarized in table 2. Overall, 9 short period of time. In addition, transfusions are asso- (90%) of 10 patients responded to the treatment: 2 ciated with a high risk of complications that may limit achieved a minor response and 7 a major response.
their effectiveness and also have a significant impact Out of these, 2, 3, 2 and 1 achieved the response within on health care cost. According to the current published the first, the 2nd, the 3rd and the 4th week respectively, data, the costs of transfusions are often overlooked and reaching a mean (±SD) Hb level of 12.6±1.5 gr/dl, underestimated, even if this approach is generally con- Table 2. Disease phase at the starting of epoetin-á and outcome.
Patient *Erytrodysplasia; VAD: vincristine, adriamycin and dexamethasone (Dex); MP: melphalan plus prednisone; APBSCT: autologous peripheral blood stem cells transplantation; IFN: interferon; CTX: cyclophosphamide; Thal + Dex: thalidomide 100-200 mg/day plus Dex 40 mg/day, D1-D4 every 4 weeks; Biphosphonates + Dex: single montly infusion of pamidronate (90 mg) or zolendronate (4 mg) plus Dex 40 mg; SD: stable disease; Prog.:progression; PR:partial remission.
sidered less expensive than other alternatives16,17. In maintenance phase iron supplementation was given contrast, epoetin is a well-known effective treatment when functional iron deficiency was present10,11.
in managing the anaemia related to MM and its dura- The importance of a rapid and effective correction ble effects and sustained benefits have been shown in of severe anaemia (Hb £8 g/dl) should not be under- a number of studies. In general, about two thirds of estimated in order to reduce the risk of transfusion patients achieve a significant haematological response and to improve the symptoms of anaemia and the pa- with the standard recommended dosage of 10.000 U tients quality of life25. This is particularly crucial for three times a week18. Alternatively, epoetin-á may be the elderly patients who are considered more vulner- administered at a dose of 40.000 U once a week14. A able. In these subjects, the haematological response dose-response effect has been clearly demonstrated19, to epoetin-á standard dosing regimen may be conside- although the correction of anaemia in some patients red clinically inadequate in order to aim a rapid and could require higher doses than those reported as ef- sustained response. In our pilot trial we tested a new fective, while the optimal dose and the dosing regi- treatment schedule with HD epoetin-á to ameliorate men are not predictable in all patients20,21. Although severe anaemia related to MM. The treatment resulted epoetin-á efficacy in the enhancement of erythropoie- in a rapid correction of anaemia in 8 out of 10 pa- sis in the large part of MM patients has been demon- tients, with a final overall response of 90%. The mean strated, there is a number of patients that do not re- Hb level rose from 8 g/dl to 12.6 g/dl after 4 week of spond to treatment22. Functional iron deficiency has treatment. Another interesting finding is the possibil- been reported as the most important cause of low re- ity to maintain a long-term haematological response sponse to epoetin-á 23,24. We included IV iron supple- with 40.000 U epoetin-á every two weeks, as we fol- mentation during TW epoetin-á administration, in lowed-up three patients. It is not absolutely clear how order to support the increased erythropoiesis. In the HD epoetin-á acts over increasingly long intervals EPOETIN ALPHA IN MULTIPLE MYELOMA-RELATED ANAEMIA between administrations. It is well known that the stan- sponse rate (90%) extends down to below 40%. We dard doses of epoetin-á, which retains the same natu- suggest that this pilot study could be used as the basis ral amino acid sequence and glycosylation seen with for the schedule of other larger trials, although did not natural hormone, administered three times a week allow us to fully support the superiority of the HD epo- stimulate the proliferation and prevent the apoptosis etin-á over the standard dose. In conclusion, this new of the colony-forming-unit-erythroid (CFU-Es). In a dosing regimen determined a rapid erythroid response recently published study on the effects of standard dos- in high percentage of patients, permitting to titrate es of epoetin-á, combined with intermittent courses of treatment as necessary to maintain stable Hb values all-trans retinoic acid in patients with myelodysplastic and suggesting that the use of HD epoetin-á could syndromes, the increase of Hb concentration in re- have an extended role in the management of anaemia sponders was found in association with higher concen- trations of BFU-Es in the peripheral blood26. Some rather biological properties of epoetin-á, such as the reported effects on the Central Nervous System27 and the antitumour activity, are still unclear and are cur- rently under investigation. In a recent study, a tenden- 1. Beguin Y, Yerna M, Loo M et al. Erythropoiesis in cy for prolongation of life in cancer patients treated multiple myeloma: Defective red cell production due to inappropriate erythropoietin production. Br J Haematol with epoetin-a has been reported28. Studies in mice MM model have shown tumour regression in response 2. Faquin WC, Schneider TJ, Goldberg MA. Effect of in- flammatory cytokines on hypoxia-induced erythropoietin Whether these aspects may really contribute to production. Blood 1992; 79: 1987-1994.
improve the management of anaemia in patients with 3. Allen A, Breen C, Yaqoob MM et al. Inhibition of CFU- MM and other lymphoproliferative disorders remain E colony formation in uremic patients with inflammato- ry disease: role of the IFN-gamma and TNF-alpha. J to be determined and deserve further clinical and bio- logical researchers, such as bone marrow culture in- 4. Koury MJ. The anemia of chronic disease: TNF-alpha vestigations and others in vitro study. Our study, in- involvement in erythroid apoptosis. Blood 2002; 100: cluding a very heterogeneous cohort of patients, most of all presenting very advanced and refractory disease 5. Goodnough LT, Skikne B, Brugnara C. Erythropoietin, and all receiving concomitant anti-myeloma treat- iron and erythropoiesis. Blood 2000; 96: 823-833.
6. Silvestris F, Tucci M, Cafforio P et al. Fas-L up regula- ments, had not been designed to detect neither these tion by highly malignant myeloma plasma cells: role in suggested effects of epoetin-á by biological studies nor the pathogenesis of anemia and disease progression.
the difference in survival, given the lack of a control population. Nevertheless, all the three patients in pla- 7. Ludwig H, Fritz E, Kotzmann H et al. Erythropoietin teau phase of disease, receiving the same maintenance treatment of anemia associated with multiple myeloma.
anti-myeloma treatment with a single monthly infu- 8. Cazzola M, Ponchio L, Beguin Y et al. Subcutaneous sion of zolendronate plus dexamethasone, showed a erythropoietin for treatment of refractory anemia in slowly but progressively increasing of the serum para- hematologic disorders. Results of a phase I/II clinical protein levels, even if in no of these the clinical fea- 9. Österborg A, Boogaerts MA, Cimino R et al. Recombi- Despite the clear limitations of our experience, nant human erythropoietin in transfusion-dependent which dont permit to draw any definitive conclusion, anemic patients with multiple myeloma and non- Hodgkins lymphoma. A randomized multicenter study.
given the limited number of patients and the inade- quate study design, the preliminary data are promis- 10. Cazzola M, Mercuriali F, Brugnara C. Use of recombi- ing. Our observations suggest that this high dose regi- nant human erythropoietin outside the setting of ure- men is safe and effective in quickly correcting severe anaemia, although the potential anti-anaemic effects 11. Rizzo JD, Lichtin AE, Woolf SH et al. Use of epoetin in of the anti-myeloma treatments may have affected the patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology haematological response. Further, the value of these and the American Society of Hematology. Blood 2002; results is limited by the fact that in a population of 10 patients the 95%-confidence limit of the observed re- 12. Ludwig H, Rai K, Blade J et al. Management of dis- ease-related anemia in patients with multiple myeloma or chronic lymphocytic leukemia:epoetin treatment rec- 21. Kasper C. Recombinant human erythropoietin in the ommendations. Hematol J 2002; 3: 121-130.
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Exelon is pleased to host the 19th annual configuration management benchmarking group conference in the chicago area june 24 -27, 2012
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