Management of Menorrhagia Associated With Chemotherapy-Induced Thrombocytopenia in Women With Hematologic Malignancy

Jill S. Bates, Pharm.D., M.S.; Larry W. Buie, Pharm.D.; C. Brock Woodis, Pharm.D.

Disclosures

Pharmacotherapy. 2011;31(11):1092-1110. 

In This Article

Prevention of Menorrhagia in Patients Receiving Myelosuppressive Chemotherapy

Severe vaginal bleeding during periods of thrombocytopenia after chemotherapy is a cause of significant morbidity. As such, therapy should focus on preventing menorrhagia from occurring. Both gonadotropin-releasing hormone analogs and oral contraceptives, which, for the purposes of this article, refer to both combined oral contraceptives and progestin-only regimens, have been used to prevent menorrhagia in premenopausalwomen who are receiving myelosuppressive chemotherapy.

Gonadotropin-releasing Hormone Analogs

One prospective cohort trial, three singlecenter descriptive prospective trials, and two retrospective reviews evaluated whether induction of amenorrhea using a GnRH analog is effective in preventing menorrhagia during periods of thrombocytopenia after chemotherapy (Table 4).[31–36]

Leuprolide acetate is a synthetic analog that acts as an agonist of the GnRH receptor. Prolonged exposure to a GnRH analog results in desensitization of its receptors. In addition, downregulation of the receptor expression will occur over time. This downregulation and desensitization process prevents stimulation of the receptor by endogenous GnRH. Thus, the synthesis and secretion of LH and FSH are shut down. A transient increase in FSH and LH levels with initial use of a GnRH analog ultimately results in a temporary increase in estradiol before desensitization and downregulation occur. Only continuous prolonged exposure to GnRH or its analog will eventually induce suppression of gonadal function.[37] The downregulation and desensitization induced by prolonged exposure to a GnRH analog is reversible with discontinuation of the agent.

Leuprolide is a synthetic peptide analog of GnRH that undergoes extensive lysis when administered orally. Therefore, when used clinically, parenteral administration is necessary. Only subcutaneous, intravenous, and intramuscular injections of leuprolide have demonstrated complete absorption of the drug. Leuprorelin acetate is the European pharmacopoeia equivalent to the product in the United States, which is commonly referred to as leuprolide.[38] Of interest, due to the nature of the biologic effect of leuprolide, the intended corollary of the drug is entirely time dependent and independent of drug dose if a minimum concentration of 1 μg/L is maintained. For the expected drug effects on sex hormones to ensue, it is necessary to provide continuous exposure to leuprolide in which concentrations are maintained above the minimum threshold.[37]

In the United States, the depot formulation of leuprolide is available as two products, one for intramuscular and one for subcutaneous injection.[39,40] The intramuscular formulation is approved by the FDA to be dosed as 3.75 or 7.5 mg every month, 11.25 or 22.5 mg every 3 months, or 30 mg every 4 months.[39] The subcutaneous formulation is dosed as 7.5 mg every month, 22.5 mg every 3 months, 30 mg every 4 months, or 45 mg every 6 months. The subcutaneous formulation is not FDA approved for use in women (it is approved for treatment of advanced prostate cancer), although many trials in women have used it.[40] Despite the fact that the intramuscular formulation is not FDA approved for subcutaneous injection, data are available suggesting that this route of administration is safe and effective.[41–47] However, adverse reactions including erythema, edema, urticaria, injection-site pain, sterile abscess, or ulceration at the injection site have been reported. Also, subcutaneous nodules or granulomas have been observed, and it is not known if this has any effect on drug absorption.[43–45,48,49]

Oral Contraceptives

Oral contraceptives have been used to prevent menorrhagia in premenopausal women who are receiving myelosuppressive chemotherapy. To our knowledge, no randomized controlled trials have assessed the safety and efficacy of this approach in this patient population. Oral contraceptive use is based on the mechanism of action of these therapies and their effect on the menstrual cycle. Many hormonal variations of oral contraceptives with continuous use induce amenorrhea and have been shown to reduce the occurrence of menorrhagia in other populations.[50,51] Thus, these agents have been used to prevent menorrhagia in premenopausal women undergoing myelosuppressive chemotherapy through hormonal alteration

Use of oral contraceptives in premenopausal woman undergoing myelosuppressive therapy is associated with many safety concerns. The estrogen component in combined oral contraceptive formulations and, to a much lesser extent, in the progestin-only regimens are associated with increased risk of thromboembolic events such as deep vein thrombosis and pulmonary embolism.[52] Cancer in and of itself is a hypercoagulable state associated with increased risk of thromboembolism. As such, combined oral contraceptive therapies that include an estrogen component are often avoided in this patient population. In addition, prolonged unopposed progestin monotherapy can lead to breakthrough bleeding secondary to induction of endometrial atrophy and ulceration.[53] Finally, oral contraceptives are associated with liver dysfunction and hepatic thrombosis, with some reports of venoocclusive disease.[54–56]

Oral contraceptives for menstrual suppression may pose adherence issues for patients with cancer receiving myelosuppressive therapy, secondary to nausea, emesis, and gastrointestinal problems such as diarrhea that may affect drug absorption.[33] Given the safety and adherence concerns, alternative therapy options for this indication are attractive, especially when considering the limitations in the evidence supporting the use of oral contraceptives in this patient population.

Clinical Studies of Gonadotropin-releasing Hormone Analogs and Oral Contraceptives

A prospective cohort study demonstrated a statistically significant difference in resumption of vaginal bleeding favoring the leuprolide study group after discontinuation of combined oral contraceptive therapy.[31] Sixteen premenopausal women with acute myeloid leukemia were included in the study. Of these, eight women received combined oral contraceptive therapy with gestodene 0.075 mg and ethinyl estradiol 0.03 mg/day. The remaining eight women received the same combined oral contraceptive regimen for a median of 16 days along with leuprolide 3.75 mg injected subcutaneously every 28 days. This overlap of therapies was intended to prevent leuprolide flare-up that often precedes the profound gonadal suppression induced by this therapy and is associated with vaginal bleeding. No statistically significant differences were observed in the frequency of vaginal bleeding (p>0.99), duration of bleeding (p=0.28), or transfusion support measures (p=0.35). No significant difference in liver toxicity was observed (p>0.99); however, only those in the combined oral contraceptive cohort experienced grade III–IV liver toxicity. After patients discontinued combined oral contraceptive therapy at the end of the study, a statistically significant increase in vaginal bleeding episodes was seen compared with those who had received leuprolide. No women in the leuprolide group experienced vaginal bleeding (p=0.009).

Although a small cohort, this study represents the only study in the cancer population, to our knowledge, for which the effectiveness of leuprolide in prevention of menorrhagia was assessed by comparison against an active control. This study illustrated the variation in which prevention of menorrhagia occurred for each of the study groups. Although the combined oral contraceptive cohort produced a rapid cessation of vaginal bleeding, leuprolide induced amenorrhea that was long lasting. A statistically significant difference in bleeding resumption was seen after discontinuation of the combined oral contraceptive therapy. This study suggests that leuprolide may be preferred for the prevention of menorrhagia in patients experiencing long periods of thrombocytopenia and receiving hepatotoxic antineoplastic treatments, such as Lasparaginase.

A prospective, open-label, noncomparative study conducted at a single center in France suggested that treatment with leuprolide may serve to attenuate vaginal bleeding in premenopausal patients receiving myelosuppressive chemotherapy.[32] In this observational study, 21 women aged 16–50 years who received chemotherapy and were anticipated to experience thrombocytopenia (defined as a platelet count < 100 × 103/mm3) were enrolled. The trial sought to clinically evaluate vaginal bleeding along with plasma levels of estradiol, FSH, and LH. Patients were initially treated with both a progestin and a GnRH analog according to the regularity of their periods and the time since the last menstrual period whenever possible. If the myelosuppressive chemotherapy could neither be scheduled nor delayed, the GnRH analog administration and progestin treatment usually began without regard to the menstrual cycle.

Leuprolide 3.75 mg was administered subcutaneously every 28 days—except for the second injection, which was administered 21 days after the first injection—until the end of chemotherapy and a stable platelet count of at least 100 × 103/mm3. If total-body irradiation was used, leuprolide treatment was stopped 2 months after irradiation, as ovarian failure secondary to totalbody irradiation was probable. In addition, nomegestrol acetate 5 mg/day was given for the first 35 days of leuprolide therapy to avoid estrogen-withdrawal bleeding. Efficacy was evaluated for all patients receiving at least two injections of leuprolide. Gynecologic evaluation took place at the beginning of treatment, every 2 months thereafter, at termination of leuprolide therapy, and at 3 and 6 months after discontinuation. Efficacy assessment included clinical evaluation for bleeding episodes and their respective magnitude, requirement for additional therapies associated with vaginal bleeding, and hormonal assays of estradiol, FSH, and LH.

Twenty patients were eligible for analysis; one patient was excluded as she received only one injection of leuprolide. One hundred three leuprolide injections were administered (median 4 injections/patient, range 1–14 injections/patient). Ten treatments were terminated early: seven secondary to total-body irradiation and three due to death associated with disease progression. Of the 20 women, 17 did not experience any clinically relevant vaginal bleeding. Overall, 19 bleeding episodes occurred in 11 women. Most of the bleeding episodes occurred before the third leuprolide injection (12 episodes). Three women required additional therapy: one who required hormone therapy after the first injection, one who prematurely stopped progestin therapy and required a platelet transfusion, and one woman with endometrial hyperplasia who required hormone therapy after the fourth leuprolide injection. Most of the bleeding episodes were short (median 3 days, range 1–23 days).

Aside from symptoms related to inhibition of the gonadal system, one subcutaneous nodule and eight superficial hematomas formed at the injection site. No injection-site reaction required treatment or contributed to patient discomfort. Lower limb pain in one woman and a hypertensive episode in another occurred during concurrent therapy with leuprolide and nomegestrol acetate. Only six women could be evaluated for ovarian hormone function. Of these women, four resumed menses and two who were amenorrheic had undergone menopause, which was confirmed by means of hormonal assay

When assessing each of the three cases in which patients experienced significant vaginal bleeding that required treatment, two of the three patients experienced bleeding that occurred after the first leuprolide injection. As such, this bleeding may be associated with the leuprolide flare-up phenomenon, which is often used to describe the temporary increase in estradiol. The third patient had endometrial hyperplasia, which was a known source of menorrhagia often unrelated to platelet count. This study demonstrated the necessity of concomitant progestin therapy after the first leuprolide injection to prevent estrogen-withdrawal bleeding, which occurs after the initial flare-up of estradiol induced by the action of leuprolide. It further supports progestin combination therapy to occur past the second leuprolide injection to completely abate estrogen-withdrawal bleeding.

These data infer that for patients who are expected to experience thrombocytopenia for a period greater than 35 days, defined in this study as a platelet count less than 100 × 103/mm3, leuprolide is effective and has a less frequent dosing interval when compared with daily oral therapies, which may serve to improve adherence. In the cancer population, this benefit of leuprolide therapy may be particularly useful for those patients who are expected to receive therapies associated with high rates of mucositis or emetogenicity that could complicate adherence to a daily oral regimen.

Similar results were demonstrated at a single institution in Rome, Italy. Thirty premenopausal women who were eligible for a bone marrow transplant (BMT) received GnRH analog therapy and were evaluated with regard to vaginal bleeding.[33] All women received conditioning regimens that contained alkylating agents. Patients received leuprolide 3.75 mg subcutaneously at least 30 days before transplantation and a second injection 28 days afterward. Ten patients reported menstrual bleeding after the first dose of leuprolide. One woman developed menstrual bleeding during the period of thrombocytopenia; however, this woman also had hemorrhagic complications at multiple sites. Twenty-eight women were evaluated at follow-up for a median of 17 months (range 3–51 mo). Two women were lost to follow-up. All 28 women developed amenorrhea, and hormonal assays at 3, 6, and 12 months after transplantation were consistent with menopause.

Another study evaluated leuprolide 7.5 mg given intramuscularly every 28 days for induction of amenorrhea before BMT.[34] Ten women were included in the study. Therapy was continued until the platelet count was maintained at greater than 50 × 103/mm3. If the platelet count decreased below 50 × 103/mm3 and a leuprolide injection was necessary, the oncologist determined whether the patient should be transfused platelets and given leuprolide intramuscularly or receive daily intravenous administrations of leuprolide 1 mg. All patients had successful induction of amenorrhea except for one patient, who was found to have a submucous myoma. No patient experienced hepatotoxicity or an increase in liver function test results attributable to therapy with leuprolide.

A focal point of this study was timing of leuprolide relative to expected thrombocytopenia. Patients received leuprolide approximately 1 month before BMT so that estrogen-withdrawal bleeding would occur during the time before the anticipated period of thrombocytopenia. The assumption with this approach is that amenorrhea would be induced and sustained before and during the period of thrombocytopenia, defined as a platelet count less than 50 × 103/mm3. All patients were determined through hormonal measurement to be gonadally suppressed before BMT.

It remains unclear as to whether elevated liver function test results thought to be associated with use of oral contraceptives or combined oral contraceptive therapy could be a function of hepatotoxic antineoplastic therapies. This study did not observe abnormal liver function test results when leuprolide was used to induce amenorrhea, which suggests that abnormal results observed in women using oral contraceptives to suppress menses after receiving hepatotoxic antineoplastic therapies are possibly attributable to the use of the oral contraceptive. No data were available in this study with regard to bleeding episodes during the period of thrombocytopenia since the trial period occurred before BMT. As such, it is not clear whether anticipated platelet counts of 50 × 103/mm3 associated with specific chemotherapeutic regimens would be a useful guide to the clinician in determining whether or not use of leuprolide to suppress menses is appropriate. However, induction of amenorrhea does imply suppression of the menstrual cycle and, therefore, menses.

A retrospective cohort study performed in Israel compared the use of no hormonal agents, depot medroxyprogesterone acetate (DMPA), and D-tryptophan-6-luteinizing hormone releasing hormone, a GnRH analog available as triptorelin, in prevention of menorrhagia in premenopausal women with thrombocytopenia (platelet count < 100 × 103/mm3) secondary to chemotherapy.[35] A total of 101 women who later developed documented severe thrombocytopenia (defined as platelet count < 25 × 103/mm3) were included in the evaluation. Twenty women received no hormone treatment, 42 patients received DMPA, and 39 received the GnRH analog. Menorrhagia was evaluated clinically and scored according to four categories ranging from no vaginal bleeding to severe vaginal bleeding.

The three cohorts were similar with respect to age, cancer diagnosis, and chemotherapy regimen. In addition, no statistically significant differences in duration of thrombocytopenia and nonvaginal bleeding were seen among the three groups. In total, 16.8% of the women experienced vaginal bleeding. Both the DMPA and GnRH analog groups had an overall lower rate of vaginal bleeding—55% and 23%, respectively—when compared with the 65% bleeding rate observed in the control cohort (those receiving no treatment). The average number of units of platelets, packed red blood cells, and fresh frozen plasma used throughout the treatment period was not significantly different among the groups. Occurrence of moderate and severe bleeding was significantly different, with no events occurring in the GnRH analog group, but occurring in 40% and 21.4% of the control and DMPA groups, respectively (p=0.002). Further, urgent treatment with conjugated estrogens to stop severe menorrhagia was indicated in the control and DMPA groups, but no treatment with conjugated estrogens was necessary for women in the GnRH analog group (p=0.004).

Thirty-four women were enrolled in a retrospective, observational study intended to ascertain whether therapy with leuprolide prevented menorrhagia during periods of severe thrombocytopenia.[36] Patients were treated with intravenous leuprolide 1 mg/day, and when the slow-release depot formulation was available, five patients were treated with leuprolide 7.5 mg given intramuscularly every month. Leuprolide therapy was discontinued in all patients when the platelet count exceeded 50 × 103/mm3. Menstrual bleeding data were assessed clinically, and patients were stratified into one of the following four categories based on severity of vaginal bleeding: no menstrual bleeding, minor vaginal bleeding resolving in less than 4 days and no therapy required, moderate-to-severe vaginal bleeding for which therapy was considered, and cases not evaluable.

Vaginal bleeding was noted to be prevented (category 1) or minimal (category 2) in 25 patients (73%). Two patients were not evaluable as blood was noted in the urine and its source could not be identified. Seven women experienced breakthrough vaginal bleeding, two of whom required estrogen therapy. The authors concluded that the best predictor of therapy success was timing of initiation of leuprolide therapy relative to onset of thrombocytopenia. This conclusion was based on the fact that 33% of women in whom leuprolide was started less than 2 weeks before thrombocytopenia developed significant menstrual bleeding versus 6% of those in whom leuprolide therapy was started earlier. There was no statistically significant difference noted in transfusion requirements when comparing the seven patients who experienced category 3 (moderate-to-severe) vaginal bleeding. No significant difference in adverse-effect profile was observed when a comparison was made with historical controls.

This study observed similar results to previous data reviewed in that leuprolide use was associated with attenuation of vaginal bleeding during periods of thrombocytopenia. Timing was demonstrated to be an important factor in therapeutic success relative to the onset of thrombocytopenia. This may be related to known estrogen-withdrawal bleeding associated with initiation of leuprolide therapy. In this study, concomitant use of progestin therapy for the first 35 days was not used. Consequently, timing may not be an influencing factor if progestin therapy was used to prevent estrogenwithdrawal bleeding.

Of note, in this study, thrombocytopenia was defined as a platelet count less than 50 × 103/mm3. However, bleeding episodes associated with initiation of leuprolide relative to the onset of thrombocytopenia were reported using a threshold of less than 20 × 103/mm3. These data may suggest that significant bleeding was not observed until a platelet count less than 20 × 103/mm3 occurred. However, the authors did not comment on the use of this platelet count threshold. Given that the biologic effect of leuprolide is time dependent and independent of drug dose if a minimum concentration is maintained, one would not anticipate use of varying dosage forms to influence clinical outcomes. Still, it may be beneficial for an institution to investigate whether use of intravenous leuprolide in place of the depot formulation would be associated with cost savings while a patient is hospitalized.

Summary and Recommendations

Several investigations performed in the setting of menorrhagia indications unrelated to thrombocytopenia evaluated the use of NSAIDs and intrauterine devices for the prevention of menorrhagia. Many reasons preclude the use of these treatment modalities in patients receiving myelosuppressive chemotherapy. Antiplatelet effects of NSAIDs impose a bleeding risk that is augmented in patients with severe thrombocytopenia.[57] As such, this may potentially worsen the clinical scenario the treatment is intended to prevent. Although intrauterine devices have demonstrated efficacy in prevention of menorrhagia, these devices are associated with increased risk of infection and group A streptococcal sepsis, which poses a serious threat to the patient expected to become neutropenic.[27]

Often, oral contraceptives are referenced as the standard therapy for menstrual suppression in premenopausal women with hematologic malignancies; however, no trials exist, to our knowledge, that have evaluated their efficacy. In addition, these agents are associated with several known adverse effects that, in the setting of malignancy, could be exacerbated by the cancer itself (e.g., thrombosis). Given the known adverse effects, difficulty with oral therapies in this patient population, and lack of controlled trial data, the evidence does not support the practice of oral contraceptive therapy for prolonged routine use to prevent menses in this patient population.

Controlled studies do exist that have evaluated the use of leuprolide in the prevention of menses in the cancer population; however, we know of no phase III trials that have investigated the use of leuprolide in prevention of menorrhagia in patients receiving myelosuppressive therapy. The trial data supporting the use of this agent are limited by small sample sizes and differing study methodologies and clinical end points; thus, it is difficult to draw conclusions from these studies. However, some commonalities among the studies do exist. For example, inclusion criteria of the studies were similar in that adult premenopausal women with hematologic malignancies, which included stem cell transplant recipients, were evaluated. This similarity suggests that this population may benefit from therapy with leuprolide.

Many factors support suppression of menses in the hematologic malignancy patient population. These patients are most likely to receive antineoplastic therapy that would produce profound thrombocytopenia. Because of the nature of therapy in this population, prolonged or cyclic profound thrombocytopenia can be expected to occur for several months. The exact platelet count threshold that when exceeded would result in major bleeding is not known. However, many practices commonly use a threshold of 10 × 103/mm3 or less to transfuse platelets in an effort to prevent major bleeding, based on the results of several large studies.[58] Risk factors exist for bleeding with higher platelet counts. One of these risk factors is refractoriness to platelet transfusion, which is typically acquired when antibodies to platelet transfusions have developed over time and with each transfusion. For this reason, limiting transfusion is beneficial in this patient population. Theoretically, prevention of platelet consumption induced by bleeding may serve to lessen the need for transfusion. Many trials evaluating leuprolide and its ability to prevent vaginal bleeding to offset the associated negative effects used a platelet count threshold of 50 × 103/mm3 or lower.[33–36]

Prophylactic therapy with a GnRH analog appears to be effective in reducing severe vaginal bleeding episodes during periods of thrombocytopenia and may possibly avoid adverse effects observed with conventional hormone therapy, such as hepatotoxicity and/or venous thromboembolism (VTE). Most of the trial data result from the use of leuprolide therapy. Overall, the trials lacked consistency with regard to dosing, dosage forms, and administration schedules. However, since the effects of these agents are independent of drug dosage, this may not be a factor that influences clinical outcomes when a minimum concentration of drug is maintained that would be observed with conventional dosages.

An advantage with regard to attenuation of severe vaginal bleeding was observed after estrogen-withdrawal bleeding occurred and when gonadal suppression was achieved.[32–36] These data suggest that use of leuprolide for prophylaxis of menorrhagia associated with thrombocytopenia mainly confers benefit in those whose period of thrombocytopenia is expected to be prolonged (i.e., > 30 days' duration). Prolonged thrombocytopenia almost always occurs in the hematologic malignancy population. The trials did observe bleeding associated with estrogen withdrawal, and this does support concomitant therapy with progestins for a defined period after initiation of leuprolide treatment, which in the trial using this methodology was 35 days.[35]

The expected action of leuprolide therapy is gonadal suppression, which leads to negligible estrogen levels for the duration of therapy. Therefore, it may be wise to consider supplementation with calcium and vitamin D in patients receiving leuprolide in order to help prevent bone mineral density losses that have occurred in women receiving leuprolide for 6 months or longer, to prevent osteoporosis.[39] Larger, phase III, randomized controlled trials are necessary to fully evaluate the safety and efficacy of leuprolide therapy to prevent menorrhagia during periods of thrombocytopenia secondary to chemotherapy.

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