Cancer Treatment

IV gammaglobulin for ITP before epidural anesthesisa.

The Cut-off platelet cound is not known. Older literature says: one hundred thousand.

While IVIG has some role in presurgical situations, plt. ct of sixty eight is probably not sufficient for the proposed surgery and would be justified. A recent review says:  "Normally, spinal or epidural anesthesia is considered safe if the platelet count is over 80,000/µl. However, the consistently low platelet counts in ITP seem to be less problematic than rapidly falling values due to other diseases, because this is often accompanied by platelet dysfunction or coagulopathy. In several studies neuraxial anesthesia was successfully performed with platelet counts between 50,000 and 80,000/µl. Nevertheless, the minimum safe platelet count for neuraxial blockade remains undefined in these patients."

 

Englbrecht JS, Pogatzki-Zahn EM, Zahn P.Spinal and epidural anesthesia in patients with hemorrhagic diathesis : Decisions on the brink of minimum evidenceAnaesthesist. 2011 Jul 31

IV gammaglobulin for ITP before epidural anesthesisa.

The Cut-off platelet cound is not known. Older literature says: one hundred thousand.

While IVIG has some role in presurgical situations, plt. ct of sixty eight is probably not sufficient for the proposed surgery and would be justified. A recent review says:  "Normally, spinal or epidural anesthesia is considered safe if the platelet count is over 80,000/µl. However, the consistently low platelet counts in ITP seem to be less problematic than rapidly falling values due to other diseases, because this is often accompanied by platelet dysfunction or coagulopathy. In several studies neuraxial anesthesia was successfully performed with platelet counts between 50,000 and 80,000/µl. Nevertheless, the minimum safe platelet count for neuraxial blockade remains undefined in these patients."

 

Englbrecht JS, Pogatzki-Zahn EM, Zahn P.Spinal and epidural anesthesia in patients with hemorrhagic diathesis : Decisions on the brink of minimum evidenceAnaesthesist. 2011 Jul 31

Nplate

Adult Immune (Idiopathic) Thrombocytopenic Purpura (ITP) is a chronic and potentially serious autoimmune disorder characterized by low platelet counts in the blood. In it, platelets are destroyed by the patient's own immune system. ITP has historically been considered a disease of platelet destruction; however, recent data also suggest that the most prominent defect is the body's inability to compensate for  platelet destruction by increasing production. Newer approaches to treating ITP fous on increasing platelet production. The U.S. Food and Drug Administration has approved Nplate (romiplostim) in August 2008. This drug is the first product that directly stimulates the bone marrow to produce needed platelets in patients with a rare blood disorder that can lead to serious bleeding. Nplate revealed a number of adverse reactions, from bone-marrow abnormalities to dangerous blood clots. A Risk Evaluation and Mitigation Strategy (REMS) has been developed to address the risks of Nplate therapy. Under the Food and Drug Administration Amendments Act of 2007, FDA has determined that a REMS is necessary for the benefits of Nplate to outweigh the risks of the product. The REMS will include a Medication Guide for patients and requires that all prescribers and patients enroll in a special program to track the long term safety of Nplate therapy.

Where a splenectomy was not performed, a recent study presented at the 14th congress of the European Hematology Association from a study comparing romiplostim (Nplate®) to the medical standard of care (SOC) in non-splenectomised patients with chronic immune thrombocytopenic purpura (ITP).
 
The study involved 234 adults with chronic ITP, who were treated with either romiplostim (n=157) or medical SOC (n=77); the latter was prescribed by the investigator according to standard institutional practices or therapeutic guidelines; the only treatments not allowed were investigational agents or other thrombopoietic agents.  A total of 13 (8%) patients who received romiplostim and 27 (35%) of those in the SOC group underwent splenectomy or discontinued the study prior to reporting a splenectomy.  Furthermore, 12% and 27% experienced treatment failure (platelet counts ≤20,000 platelets/microL for four consecutive weeks, a major bleeding event, and/or a change in therapy due to intolerable side effects or bleeding symptoms) or discontinued the study, respectively. 

Where a splenectomy was not performed, a recent study presented at the 14th congress of the European Hematology Association from a study comparing romiplostim (Nplate®) to the medical standard of care (SOC) in non-splenectomised patients with chronic immune thrombocytopenic purpura (ITP).
 
The study involved 234 adults with chronic ITP, who were treated with either romiplostim (n=157) or medical SOC (n=77); the latter was prescribed by the investigator according to standard institutional practices or therapeutic guidelines; the only treatments not allowed were investigational agents or other thrombopoietic agents.  A total of 13 (8%) patients who received romiplostim and 27 (35%) of those in the SOC group underwent splenectomy or discontinued the study prior to reporting a splenectomy.  Furthermore, 12% and 27% experienced treatment failure (platelet counts ≤20,000 platelets/microL for four consecutive weeks, a major bleeding event, and/or a change in therapy due to intolerable side effects or bleeding symptoms) or discontinued the study, respectively. 

http://www.fda.gov/cder/foi/label/2008/125268lbl.pdf

Prescribing information

http://www.nelm.nhs.uk/en/NeLM-Area/News/2009---June/09/Conference-report-Romiplostim-Nplate-in-chronic-ITP-/

Nplate™ used to be only available through the Nplate™ NEXUS (Network of Experts Understanding and Supporting Nplate™ and patients) Program. This program is designed to promote informed risk-benefit decisions before initiating treatment and while patients are on treatment to assure appropriate use of Nplate™ in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. However, in 2011 this requirement had been suspended. Caution in using Nplate is still warranted.

Nplate™ should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. It should not be used in an attempt to normalize platelet counts. Nplate™ is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP.

http://www.fda.gov/cder/foi/label/2008/125268lbl.pdf

1. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: A double-blind randomised controlled trial. Lancet. 2008;371(9610):395-403.
2. Stasi R, Evangelista ML, Amadori S. Novel thrombopoietic agents: A review of their use in idiopathic thrombocytopenic purpura. Drugs. 2008;68(7):901-912.
3. Tiu RV, Sekeres MA. The role of AMG-531 in the treatment of thrombocytopenia in idiopathic thrombocytopenic purpura and myelodysplastic syndromes. Expert Opin Biol Ther. 2008;8(7):1021-1030.

Cyclosporin for ITP

There are patients with refractory autoimmune thrombocytopenia do not respond to standard therapy with high-dose corticosteroids, WinRHO, Rituxan, IVGG, and splenectomy. Cyclosporin is useful for some patients who occasionally respond to it. There are many published case reports of its effectiveness. It is recommended for refractory cases in standard reviews.

Since very few pateints are this refractory, prospective studies are not possible but cyclosporine is widely accepted, including being mentioned in compenida for off-label use for Evan's syndrome which is a combination of immune thrombocytopenia and hemolytic anemia.

D B. Cines and J. B. Bussel
How I treat idiopathic thrombocytopenic purpura (ITP)
Blood, October 1, 2005; 106(7): 2244 - 2251.

Kappers-Klunne MC, van't Veer MB. Cyclosporin A for the treatment of patients with chronic idiopathic thrombocytopenia purpura refractory to corticosteroids or splenectomy. Br J Haematol. 2001;114: 121-125

Bourgeois E, Caulier MT, Delarozee C, et al. Long-term follow-up of chronic autoimmune thrombocytopenic purpura refractory to splenectomy: a prospective analysis. Br J Haematol. 2003;120:1079-1088

WinRho for Immune Thrombocytopenic Purpura (ITP)

Immune (or idiopathic) thrombocytopenic purpura (ITP) is commonly encountered by the practicing hematologist. Clinical management decisions have traditionally been guided by individual training and past experience. Input from the literature has been more from observational reports of case series than from scientific results of hypothesis-driven research. Practice guidelines and several surveys of clinical hematology practice have highlighted important questions in the field, and in the past 5 to 10 years both clinical and laboratory investigations have produced valuable new information, especially about options in refractory disease. Unfortunately, the last comprehensive guideline  have been published a decade ago.

Generally, the standard of practice for patients who cannot maintain an adequate platelet count on tapering steroids is to undergo splenectomy. In 60% to 70% of patients this restores a normal platelet count for at least 5 to 10 years. It allows those patients who respond to this procedure to avoid both the risks of low platelet counts and the toxicity of daily steroids. However, although both the site of platelet destruction and the response to intravenous immunoglobulin (IVIG) have been suggested to predict response to splenectomy, there is no universally acknowledged way to predict which patients will respond. SOme patients do not respond and otehrs relapse, sometimes due to a regrowth of accessory spleen tissue. WHen clearly identifeid, an accessory spleen should be removed, if spenectomy reviously resulted in a remission. However, the decision  to repeat what is now an open splenectomy is fraught with uncertainty. Patients are often reluctant to be exposed to the inherent risks of surgery and the small but significant risk of overwhelming sepsis after splenectomy without a guarantee of success. It is acceptable to proceed with other therapies at that point. Anti-RhD is one such option.

IV anti-D is a safe and effective treatment in approximately two thirds of Rh+, nonsplenectomized adults with ITP and can be used as a steroid-sparing agent. There is no reason to believe that anti-D is curative or that it affected the natural history of the ITP in these adults. Rather, it appeared to give patients time to improve on their own.

George JN, Woolf SH, Raskob GE, et al. Idiopathic Thrombocytopenic Purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood. 1996;88:3–40.

Cines DB, Bussel JB. How I treat idiopathic thrombocytopenic purpura (ITP). Blood. 2004;106:2244–2251.

Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995–1008

Cooper N, Woloski BMR, Fodero EM, Novoa M, Leber M, Bussel JB. Does treatment with intermittent infusions of IV anti-D allow a proportion of adults with recently diagnosed immune thrombocytopenic purpura (ITP) to avoid splenectomy? Blood. 2002;99: 1922

Rituximab for ITP

The state of the field regarding Rituxan in ITP until recently has been sceptical because only case reports and case series have been reported. Publication bias leads to under-reporting of negative results and over-reporting of positive results. In three large cohorts of adults who had failed multiple therapeutic modalities, patients were treated with the regimen of anti-CD20 used to treat B-cell lymphoma—375 mg/m2 weekly for 4 weeks. Approximately 50% of patients had a partial or complete response, and about 33% had durable remissions. However more recently a prospective study in the pediatric population rvealed a 31% response rate. Rituximab for other than first line has been recommended in a recent treatment review in a major journal and is being increasingly used. Medicare lists it as reimbursable.

A recent critical review states: "While these studies clearly document the therapeutic efficacy of rituximab in chronic, refractory ITP in both adults and children, we still do not know which ITP patients should receive rituximab therapy. ...further trials are definitively needed in order to determine the place of rituximab in the treatment of ITP." However, it is generally accepted that some patients can benefit from Rituxan and obtain long term remissions of their disease. There is no consensus on whether maintenance Rituxan should be continued after response and common practice is to wait for relapse to retreat.

A 2007 review concluded: "Rituximab resulted in an overall platelet count response in 62.5% of adults with ITP. However, this finding derives from uncontrolled studies that also reported significant toxicities, including death in 2.9% of cases. These data suggest that providers should avoid indiscriminate use of rituximab and that randomized, controlled trials of rituximab for ITP are urgently needed. " Patients have been reported who develped PML (Progressive Multifocal Leukoencephalopathy".

Carson, K et al, “Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.” Blood. 2009 May 14;113 (20):4834-40

Donald M. Arnold, MD, MSc; Francesco Dentali, MD; Mark A. Crowther, MD, MSc; Ralph M. Meyer, MD; Richard J. Cook, PhD; Christopher Sigouin, MSc; Graeme A. Fraser, MD; Wendy Lim, MD, MSc; and John G. Kelton, MD Systematic Review: Efficacy and Safety of Rituximab for Adults with Idiopathic Thrombocytopenic Purpura Ann INtern Med 2 January 2007 | Volume 146 Issue 1 | Pages 25-33

Stas et al, Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura Blood, 15 August 2001, Vol. 98, No. 4, pp. 952-957

Idiopathic Thrombocytopenic Purpura (ITP) and Anti-CD20 Monoclonal Antibody: A Case Report.
Clinical and Applied Thrombosis/Hemostasis, October 1, 2006; 12(4): 489 - 492

S. Berentsen
Rituximab for the treatment of autoimmune cytopenias
Haematologica, December 1, 2007; 92(12): 1589 - 1596.

M. Ruggeri, S. Fortuna, and F. Rodeghiero
Heterogeneity of terminology and clinical definitions in adult idiopathic thrombocytopenic purpura: a critical appraisal from a systematic review of the literature
Haematologica, January 1, 2008; 93(1): 98 - 103.
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C. M. Bennett, Z. R. Rogers, D. D. Kinnamon, J. B. Bussel, D. H. Mahoney, T. C. Abshire, H. Sawaf, T. B. Moore, M. L. Loh, B. E. Glader, M. C. McCarthy, B. U. Mueller, T. A. Olson, A. N. Lorenzana, W. C. Mentzer, G. R. Buchanan, H. A. Feldman, E. J. Neufeld, and the Pediatric Rituximab/ITP Study Group and the Gl
Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura
Blood, April 1, 2006; 107(7): 2639 - 2642

Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood. 2001;98:952–957.

Cooper N, Stasi R, Cunningham-Rundles S, et al. The efficacy and safety of B-cell depletion with anti-CD20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura. Br J Haematol. 2004;125:232–239.

Braendstrup P, Bjerrum OW, Nielsen OJ, et al. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura. Am J Hematol. 2005;78:275–280.

A. L. Perrotta Re-treatment of Chronic Idiopathic Thrombocytopenic Purpura With Rituximab: Literature Review Clinical and Applied Thrombosis/Hemostasis, January 1, 2006; 12(1): 97 - 100.

D. B. Cines and J. B. Bussel How I treat idiopathic thrombocytopenic purpura (ITP)
Blood, October 1, 2005; 106(7): 2244 - 2251.

Intravenous gammaglobulin for ITP

Lay Summary: IVIG is standard for ITP but represents a "holding action" rather than a cure.

IVIG is approved by the FDA for use in the treatment of the following diseases: Kawasaki disease, dermato/polymyositis, idiopathic thrombocytopenic purpura (ITP), Guillain-Barre syndrome, polyneuropathy, some viral diseases, and some forms of immune deficiency. The place of IVIG in the treatment of ITP is not well clarified. It does not modify the disease as do steroids and splenectomy, but only gains a temporary rise in platelet counts, until definitive therapy can be planned or accomplished. There are ongoing shortage that jeopardize long term therapy. In addition, a number of alternatives exist, including: Anti-RhoD, vincristine, Rituximab, danazol, high dose pulse steroids and even chemotherapy. IVIG is accordingly best used as a temporary measure, to prepare the patient for spenectomy or while discussions of other treatments take place. It is also occasionally used to wait and see if a spontaneous remission of theITP occurrs; however, this use is less supported by the literature.
Based on the literature, CMS advises the following:IVIG is indicated for chronic ITP only when all of the following conditions are met:

Prior treatment with corticosteroids and splenectomy;
Duration of illness less than 6 months;
Age of 10 years or older;
No concurrent illness/disease explaining thrombocytopenia; and
Platelet counts persistently at or below 20,000/ml.

The AUstralian guideline sets the plt. level at 30K and addes preoperative use and use in preagnant women as well as for severe bleeding and other indications.

Anderson D, Ali K, Blanchette V, et al. Guidelines on the use of intravenous immune globulin for hematologic conditions. Transfus Med Rev. 2007;21(2 Suppl 1):S9-56.

George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, Blanchette VS, Bussel JB, Cines DB, Kelton JG, Lichtin AE, McMillan R, Okerbloom JA, Regan DH, Warrier I: Idiopathic thrombocytopenic purpura: A practice guideline developed by explicit methods for the American Society of Hematology. Blood 88:3, 1996

Download 2011 ITP Pocket Guide[1]

Cines DB, Blanchette VS: Immune thrombocytopenic purpura. N Engl J Med 2002 Mar 28; 346(13): 995-1008

Kahn MJ, McCrae KR: Splenectomy in Immune Thrombocytopenic Purpura: Recent Controversies and Long-term Outcomes. Curr Hematol Rep 2004 Sep; 3(5): 317-23

McMillan R, Durette C: Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood 2004 Aug 15; 104(4): 956-60

Australian Guideline(2007)

http://www.nba.gov.au/ivig/pdf/criteria-qrg.pdf

Alan H. Lazarus^{* Mechanism of action of IVIG in ITP} 2002 Blackwell Science Ltd  Vox Sanguinis Volume 83, Issue Supplement s1, pages 53–55, August 2002