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More on a Young Woman With Abrupt-Onset Mucocutaneous Bleeding: Treatment Choices

Volume 58 - Issue 11 - November 2018

Author:
Ronald N. Rubin, MD—Series Editor

Citation:
RN. More on a young woman with abrupt-onset of mucocutaneous bleeding: treatment choices. Consultant. 2018;58(11):313-315.

 

Last issue’s article presented the case of a 32-year-old woman who was referred by her dentist for evaluation of a possible bleeding disorder.1 She had begun to notice gum bleeding of unusual severity with brushing, but the dentist detected no periodontal disease and noted easy bleeding induced by probing anywhere in the mouth, as well as the presence of several purpuric lesions under the tongue. After the results of a complete blood cell count (CBC) showed a strikingly low platelet count of 19,000/µL, the woman eventually received a diagnosis of adult immune thrombocytopenia (which is also still referred to as idiopathic thrombocytopenic purpura, or ITP).

She was prescribed a course of prednisone, 1 mg/kg orally, and received a 2-day outpatient infusion of intravenous immunoglobulin (IVIG); by day 5, her platelet count had risen to 52,000/µL, and at 1 had month peaked at 79,000/µL. All evidence of mucocutaneous bleeding ceased.

After 4 weeks, a steroid taper was initiated, but within a month the platelets had decreased to less than 50,000/µL, and at 3 months were once again in the 20,000/µL range and on occasion less than that. Although her thrombocytopenia was not as significant as at the time of first presentation, some skin bruising was again evident. Thus a repeat course of a steroid—this time high-dose dexamethasone—was given, with a similar timing and extent of platelet response. The dexamethasone regimen was repeated twice, and the platelets remained above 50,000/µL for 6 months. Nevertheless, thereafter the outpatient platelet counts began to decrease again to numbers similar to those at presentation.

She presented for reevaluation, at which time a bone marrow examination was performed, the results of which showed normal cell morphology and adequate megakaryocytes, findings that were consistent with and confirmatory of the ITP diagnosis.

 

Find Out!

Answer: A is the strategy least likely to result in long-term remission of the patient’s ITP.

Management of adult ITP is a still-evolving amalgam of time-tested strategies admixed with the new immunomodulators and biologics that are so exciting in the realm of hematology/oncology. Before discussing the specifics and paradigm, however, a discussion of tactics and strategy is required.

The ultimate strategic goal is to “cure,” or at least attain long-term control (“remission”) of the process with the greatest efficacy and the least toxicity. And, of course, cost and convenience are also important considerations. However, at presentation, we encounter a patient who has a significantly and perhaps dangerously lowered platelet count who may already be manifesting some degree of overt bleeding. So at this time, the immediate strategic goal is to quickly raise the platelet count to a safer level—a commonly used milestone is greater than 50,000/µL2—even if that treatment is less effective in the long run.

In this regard, 2 therapies have long and well-defined track records—corticosteroids and IVIG. Corticosteroid therapy at least transiently stuns and slows the immune system’s synthesis of antibody to platelets, as well as T-cell and macrophage platelet destruction, while IVIG is thought to competitively occupy autoantibody platelet binding and receptor sites, thus protecting against immune destruction. There are many ongoing disputes about which corticosteroid regimen works best and at what dosage. The remaining contenders are traditional prednisone, 1 mg/kg for a month then with a taper, and the newer high-dose dexamethasone (40 mg/day for 4 days, either once or in a series of 6 monthly cycles).2-4 Suffice it to say that both steroids induce a response usually within 7 to 10 days in most patients (50%-90%), but only a minority (roughly a third) of patients remain in remission once the steroids are stopped, and even fewer attain longer-term remission.3,4 Meanwhile, IVIG will induce an increase in platelets in a higher number of patients, up to 85%, and usually even more quickly. But as would be expected with an immunoglobulin being catabolized, the effect essentially erodes uniformly by day 21. Each infusion is thus a transient event, such as taking acetaminophen for a headache. Remember, however, the immediate tactical goal is to quickly raise the platelet count to a safe level, and both these maneuvers do so.

In agreement with many authorities, I use both approaches—the traditional prednisone regimen and IVIG—in patients with ITP who have a platelet count less than 20,000/µL, with the immediate goal of quick platelet response and with the hope that the patient is among the 1 in 3 in whom the course of steroids effects a long-term remission. That is what was done in the case of the patient presented above—in fact, 3 times in 6 months—and although the interventions did their temporary job, it is time to consider other strategies, and Answer A is the least optimal choice here.

Happily, a variety of second-line therapy maneuvers appear capable of quite satisfactory long-term control of ITP. In order of their historical use and evaluation, these maneuvers are splenectomy, the immunomodulatory agent rituximab, and the newer synthetic thrombopoietin receptor agonists (TPO-RAs) eltrombopag and romiplostim.

In previous decades, essentially the only second-line therapy for ITP was splenectomy, which was the routine. Splenectomy was commonly performed as the “hematologist’s operation”—long-term control of ITP, management of certain hemolytic conditions, staging of Hodgkin disease, and diagnosis of lymphomas. Its use has continued to wax and wane as newer and less-invasive therapies challenge its role, while laparoscopic techniques and efficacious vaccination has rendered splenectomy far easier and safer. The current facts about splenectomy are as follows: 5-year-plus response rates are a solid 60% to 70%, far higher than with steroids or rituximab.5 A variety of surgical complications (eg, bleeding, infection, thromboembolism) occur early in approximately 15% of cases. And, of course, the risk of post-splenectomy sepsis exists, but the overall risk of mortality from overwhelming sepsis is very small—0.73 per 1000 patient-years.5,6 It would seem splenectomy’s bark is far worse than its bite in today’s medicine, yet recent data indicate that fewer than 25% of patients with ITP undergo splenectomy despite the favorable response rates.5 At 5 years, surgical mortality is less than 0.2%, surgery-related complications are 9.6%, and the cost comparison with rituximab or TPO-RA is very favorable.6 Thus splenectomy (Answer D) would be a very acceptable therapy for our patient.

Rituximab (Answer B) also has been used in refractory relapsed cases of ITP. This immunomodulatory drug is given in varying dosage schedules as a course of 4 weekly intravenous infusions. Initial response rates are quite good at 50% to 60%, although the longer-term response decays to 25% at 5 years.3,7 Many practitioners will give repeated courses at intervals to sustain the response, requiring intravenous infusions and incurring considerable cost, but overall rituximab is well tolerated. It is an acceptable alternative for long-term control in relapsed recurring ITP.

Finally, the newer thrombopoietic agents (Answer C) are now in the armamentarium for the long-term management of ITP. There are 2 TPO-RAs, the intravenous preparation romiplostim, and the oral preparation eltrombopag. In difficult patient populations (eg, post-splenectomy, rituximab failures), these medicines can still result in 80% overall response rates that are durable with continuing therapy, and with apparently small numbers of tolerable and non–life-threatening adverse effects such as transaminase elevations and headache.3,8 The major difficulty is economic, with a price tag usually exceeding $100,000 annually.5 Still, from a medication standpoint, TPO-RAs are a solid treatment option for our patient.

So regarding the question above, the weakest (and thus incorrect) choice is Answer A , continuing to chase repeated bouts of thrombocytopenia with a combination that can, with great efficacy, temporarily boost dangerous platelet counts to safe levels but that offers very little long-term control with ever-increasing steroid toxicity. The other 3 choices are superior in that regard. Ongoing experience with trials in time may result in one obvious best choice. Patient characteristics (eg, can a patient tolerate even today’s splenectomy), patient preference, and economics help determine the best approach in a given case.

Here is the essence of what is so important in ITP management: short-term tactics vs long-term strategy. And with any of these therapies, it must be remembered that a normal platelet count is not required. The target for maintenance is a count greater than 30,000/µL, except on rare occasions such as major surgery or neurosurgery, when greater than 100,000/µL is recommended. None of these maneuvers need be pushed toward higher numbers for the sake of “normality” every day.

NEXT: Patient Follow-Up

Patient Follow-Up

The patient continued to respond marginally to courses of prednisone and IVIG, with platelet counts increasing to 30,000 to 50,000/µL but then decaying within several months. Other options were offered and discussed in detail. The patient, being a young and healthy person, chose splenectomy with the hope that she would respond well with solid long-term control and no need for further treatment. She believed, as did her health care team, that rituximab and TPO-RAs would be available in the future if needed. After receiving the appropriate immunizations, she underwent an uncomplicated laparoscopic splenectomy. At 1 week, her platelet count was 190,000/µL, and it has settled into the 150,000/µL range 2 years out.

Ronald N. Rubin, MD, is a professor of medicine at the Lewis Katz School of Medicine at Temple University and is chief of clinical hematology in the Department of Medicine at Temple University Hospital in Philadelphia, Pennsylvania.

References:

  1. Rubin RN. A young woman with abrupt onset of mucocutaneous bleeding. Consultant. 2018;58(10):279-280, 282.
  2. Cines DB, Bussel JB. How I treat idiopathic thrombocytopenic purpura (ITP). Blood. 2005;106(7):2244-2251.
  3. Lampert MP, Gernsheimer TB. Clinical updates in adult immune thrombocytopenia. Blood. 2017;129(21):2829-2835.
  4. Wei Y, Ji X-b, Wang Y-w, et al. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood. 2016;127(3):296-302.
  5. Chaturvedi S, Arnold DM, McCrae KR. Splenectomy for immune thrombocytopenia: down but not out. Blood. 2018;131(11):1172-1182.
  6. Ahmed R, Devasia AJ, Viswabanoya A, et al. Long-term outcome following splenectomy for chronic and persistent immune thrombocytopenia (ITP) in adults and children: splenectomy in ITP. Ann Hematol. 2016;95(9):1429-1434.
  7. Ghanima W, Khelif A, Waage A, et al; RITP Study Group. Rituximab as second-line treatment for adult immune thrombocytopenia (The RITP trial): A multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9978):1653-1661.
  8. Saleh MN, Bussel JB, Chang G, et al; EXTEND Study Group. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013;121(3):537-545.