Danazol therapy combined with intermittent application of chemotherapy induces lasting remission in myeloproliferative disorder (MPD): an alternative for the elderly with advanced MPD

Abstract

There is no good alternative therapy available for elderly patients with advanced myeloproliferative disorders (MPD) who failed on conventional therapies and are not candidates for bone marrow transplant. We report here an effective therapy that induced exceptionally long‐lasting remissions and improved quality of life. Eighteen elderly patients (mean age: 70·6 years) (16 myelofibrosis and 2 thrombocythemia) who had failed on conventional therapies were treated. Danazol was administered daily at 200–800 mg throughout the study. Chemotherapy was applied intermittently as needed to reduce spleen size and blood counts. Busulfan (2–4 mg/day) was used most often and 6‐mercaptopurine (6‐MP) (50–100 mg/day) and/or cytarabine (100–200 mg/m²) if the white blood cell (WBC) count rose rapidly. When MPD stabilized, chemotherapy was discontinued and dosage of danazol was reduced. Therapy was well tolerated. Overall, 61% of patients responded with unexpectedly long‐lasting remissions and improved quality of life. Three (17%) had excellent (E) response, defined by normalization of blood counts and non‐palpable spleen, while eight (44%) had good (G) response, defined by rise of Hct by ⩾7% and ⩾50% reduction of spleen. Mean duration of remission was 45 months (10–78 months) in E responders and 11 months in G responders (2–22 months). This regimen offers a safe and effective alternative for advanced MPD in the elderly.

Keywords:

• MPD
• Danazol
• Splenomegaly
• Busulfan

Introduction

Chronic myeloproliferative disorders (MPD) are a group of clonal disorders of stem cells in which genetic mutations of the multipotential stem cells leads to over‐proliferation of one or more components of hematopoetic cells. It encompasses polycythemia vera, essential thrombocythemia (ET), and idiopathic myelofibrosis (MF). Chronic myelocytic leukemia is often cited as a separate entity.1 Splenomegaly due to extramedullary hematopoiesis is a common feature and spleen size often reflects disease activity.1 The clinical course of MPD is variable but in late stages, bone marrow failure develops requiring frequent blood transfusions, and it may transform into acute leukemia, one of the causes of death in MPD.1

Massive splenomegaly is responsible for a reduction in all blood counts, abdominal pain and discomfort, and systemic symptoms such as severe lethargy, night sweats, and weight loss. For management of symptomatic splenomegaly associated with MPD, splenectomy,2 splenic irradiation,3 and high doses of steroids4 were used with limited success.

Although treatment is usually palliative,1 management of MPD comprises phlebotomy to decrease red cell mass, chemotherapy such as hydroxyurea or alkylating agents, or interferon to control expansion of the clone, and anagrelide to control thrombocytosis.1 Hydroxyurea is most widely used1 but other chemotherapeutic agents such as 2‐chlorodeoxyadenosine,5 melphalan,6 IFN‐alpha,7 thalidomide,8 imitanib mesylate,9 and farnesyl transferase inhibitors10 have also been introduced.

Recently, bone marrow transplant (BMT) has been used with some success in MPD, particularly in young patients,11 and offers the only potentially curative therapy for MPD. BMT is, however, associated with high morbidity and mortality and therefore is limited mainly to younger patients.11 MPD most commonly afflicts the elderly, most of whom are not good candidates for BMT because of age and co‐morbidities. The age group >60 years has been associated with poorer prognosis of MPD,12,13 but few options are available to those elderly patients with advanced intractable MPD. There is an urgent need for alternative therapy for this group of patients.

We report here successful outcome of a new regimen, which consists of continuous administration of danazol with intermittent application of chemotherapy. It induced long‐lasting remission and remarkable improvement of quality of life. We recommend it as a good alternative therapy to those groups of elderly patients in which little therapy can be offered except frequent blood transfusions, hospitalization, and hospice care.

Materials and Methods

Eighteen patients with MPD were studied, 11 females and 7 males. Most were elderly with mean age of 70·6 years (Table 1). Sixteen had MF and two had ET. All had advanced MPD with splenomegaly. In eight patients, the spleen was massive, occupying the entire abdomen on palpation.

Table 1. Data on all patients and subgroup analysis of excellent (E), good (G), and poor (P) responders are shown

		Excellent	Good	Poor
	Total	(E)	(G)	(P)
No.	18	3	8	7
Mean age (years old)	70·6	75	66·4	74
Sex (M/F)	7/11	0/3	3/5	4/3
MPD type	16 MF, 3 ET	3 MF	7 MF, 1ET	6 MF, 1ET
MPD duration (year)	12·6	7·0	16·4	10·3

Note: MF, myelofibrosis; ET, essential thrombocythemia.

Danazol (200–800 mg) was administered daily through the course of the study period. Dosage was periodically adjusted according to subjective tolerance or liver function abnormalities. Upon remission, danazol was decreased to either 200 mg/day or 2–3 times a week.

Chemotherapy was administered intermittently to reduce the size of spleen and the blood count. Oral busulfan (2–4 mg/day) was most often employed; 14 received it for 1–30 months intermittently. Oral 6‐mercaptopurine (6‐MP; 50–100 mg/day) was added in seven patients for 1–3 months, and i.v. cytarabine (100–200 mg/m²) was used in five patients for 5 days during rapid rise of white blood cell (WBC) count. Upon remission, chemotherapy was discontinued, but was resumed if signs of relapse were noted as demonstrated by an increasing splenomegaly and/or rising WBC count.

Patients were followed with blood counts, liver function tests, and blood chemistry. Spleen size was monitored by physical examination and was measured by CAT scans in eight patients. Performance status, general well‐being, side effects of therapy, and any complications of MPD were evaluated at each clinic visit.

Responses were classified as excellent (E) if blood counts normalized and spleen was no longer palpable for at least 6 months; good (G) if spleen size was reduced by 50%, hemoglobin normalized, or Hct rose by 7%, and/or platelet counts rose to 100 000/l for at least 2 months and poor (P) if none of the above criteria was met.

Results

Overall response rate (Excellent and Good) was 61% with danazol and intermittent chemotherapy. Seven were considered failures by the criteria stated.

Three patients (17%; cases 1–3) had excellent (E) responses, having achieved complete remission as defined, have been maintained for 78, 54 and 26 months. Their mean duration of remission was 45 months. Eight patients (44%) had good (G) responses as defined and the mean duration of remission was 11 months. Table 2 summarizes data on duration of responses and treatment period among subgroups of responders.

Table 2. Data on treatment period and duration of remission of excellent (E), good (G), and poor (P) responders are summarized

	Excellent	Good	Poor
No.	3	8	7
Treatment period (month)	6–30	1–21	1–9
Mean	14	7	4
Remission duration (month)	10–78	2–22	1–15
Mean	45	11	7

Excellent (E) responders

All three of the E responders were treated with daily danazol, 200–800 mg/day. Busulfan intermittently was added to danazol for 6–30 months (mean: 14 months). In one case, busulfan was given in combination with 6‐MP for 2 months or with cytarabine for 5 days, when WBC count rose rapidly. Range of duration of remission was 10–78 months (mean: 45 months). Relapses occurred after 4–60 months (mean: 31 months) post‐discontinuation of chemotherapy. Re‐treatment with chemotherapy induced another remission. Two of the E responders (cases 1 and 2) are further described in the section on ‘Representative case studies’ below.

Good (G) responders

Of the eight G responders, three were treated with busulfan, two with busulfan and 6‐MP, and one with busulfan, 6‐MP, and cytarabine.

Four patients presented initially with massive splenomegaly and/or hepatomegaly. The spleen occupied most of the abdomen and the tip palpable just above pubic rim. With combined therapy, the spleen became impalpable in three cases and in a further five cases, it was reduced by about 50%. Duration of chemotherapy ranged from 1 to 21 months (mean: 7 months). Duration of remission ranged from 2 to 22 months (mean: 11 months). Relapses occurred after 1–12 months (mean: 8 months) after discontinuation of chemotherapy. Re‐treatment with chemotherapy plus danazol induced another remission.

Poor (P) responders

Among the seven poor responders, three patients had some improvement but did not meet the criteria of G responders as described in the section on ‘Materials and Methods’. The remaining four patients did not show any improvement in hematological picture or size of spleen.

Therapy was well tolerated in all; however, chemotherapy induced mild bone marrow suppression in 14 patients, which was reversible. Mild elevation of liver function tests was observed in this study but all returned to normal by decreasing the dosage of danazol or withholding it for 1 month. None had serious complications. Two patients developed acute leukemia within 3 years of follow‐up.

Representative case studies

Case 1 (Excellent response)

A 76‐year‐old woman with 4‐year history of polycythemia vera had been treated with phlebotomy and alkylating agents. She developed severe pruritus over a 2‐year period which was refractory to all attempted treatments which were administered by several specialists. It became increasingly intense, particularly after bathing, which she described as unbearable, depriving her of rest, and patient reported contemplating suicide. When first seen at our clinic (March 1988), she had Hct 46%, platelet count 744 000/μl, leukocyte count 25 800/μl with 5% eosinophils, and 2% basophils. After 1 week of danazol 600–800 mg/day, she reported first relief from the agony of pruritis, sleeping well, and daring to bathe. However, each time she stopped danazol, her itching returned; therefore, she ultimately continued danazol for 18 year. Initially, she also took busulfan for 2·5 years but had to stop it due to pancytopenia. However, her remission after discontinuing busulfan lasted 4 year. In November 1994, she resumed busulfan for 6 months due to rising leukocytes. Her second remission after stopping the second cycle of busulfan lasted 2 year, and for the next 10 years, she took busulfan sporadically to control white blood cell counts and splenomegaly, and occasional others (6‐MP for 2 months in 2000, and cytosine arabinoside for 5 days in 2002) for rising white blood cell counts. She required reduced danazol during the last 10 years. Surprisingly, her MPD remained under excellent control for 18 years with danazol and intermittent chemotherapy.14

Case 2 (Excellent response)

A 72‐year‐old white woman had diagnosis of MPD in 1988 and had been treated with hydroxyurea for 15 years with satisfactory response until April 2003 when she became refractory with signs of progression of the disease, increasing splenomegaly, left upper quadrant pain and discomfort, and progressive anemia and thrombocytopenia. Recombinant erythropietin failed to improve her anemia. She received nine cycles of radiation therapy to reduce the spleen size and to relieve splenic pain. CT of abdomen 4 months later revealed reduction of spleen size and improvement of splenic pain and thrombocytopenia. However, 4 months later, the spleen increased again along with splenic pain, increasing lethargy, weight loss, and severe night sweats and difficulties carrying on her daily activity. When she was first seen at our clinic, massive hepatomegaly and splenomegaly were noted. The spleen occupied most of left side of abdomen and spleen tip was palpable above left inguinal region of pelvis. It measured 23·6 cm and liver was 19 cm below costal margin. Blood counts showed Hgb 10·5 g/dl, WBC count 13 900, and platelet counts 202 000. In January 2004, danazol was begun (600 mg/day) along with busulfan (2–4 mg/day). After 6 months of this combined therapy (May 2005), liver was no longer palpable and tip of spleen was palpable below the left costal margin. Serial CT scans confirmed marked reduction of splenomegaly. Blood counts showed Hgb 14·4, WBC count 5500, and platelet count 118 000. She was able to resume her full activity and become independent and able to carry out her duties as housewife. Busulphan was discontinued because of thrombocytopenia. In February 2005, blood counts showed Hgb 14·2, WBC count 6800, and platelet count 294 000, and spleen was no longer palpable. Her remission has now been maintained with danazol alone for 1·5 years. She has regained her strength and appears in complete remission.

Discussion

There is no good alternative therapy available for elderly patients with advanced MPD who failed on conventional therapy and are not candidates for bone marrow transplant. Danazol therapy combined with intermittent application of chemotherapy offers a new effective and safe alternative to this group of patients. Remissions induced by the combined therapy were characterized by reduction of spleen size and improvement of blood counts. In E and G responders, remissions were maintained for prolonged periods and ranged from 1 to 60 months (mean: 18 months) with danazol alone after discontinuation of chemotherapy. Danazol with sporadic application of chemotherapy appears particularly effective in reducing splenomegaly and improving their quality of life.

The efficacy of danazol in MPD was previously reported by other investigators15^–17 and busulfan was widely employed in the treatment of MPD. Combined use of the two drugs in the present study revealed exceptionally long‐lasting un‐maintained remission even after discontinuation of chemotherapy and that often lasted several years. Such a long remission, without maintenance chemotherapy, has not been reported with danazol or busulfan alone.

The benefit of androgens in MPD has been documented in the literature and chromosome study enabled prediction of response.18 Oxymetholone has been used for MPD with anemia and thrombocytopenia.19 It is interesting to note that all E responders in our study were female, and that both the duration of their therapy and of their remissions were longer compared to G and P responders.

Danazol is an attenuated androgen (reduced masculinizing effects) initially formulated to treat women with endometriosis.20 It was subsequently found effective in immune thrombocytopenic purpura and other autoimmune disorders.21,22 We reported use of danazol for the successful treatment of refractory pruritus associated with MPD14 and others have confirmed our observation.23 In our study, an elderly woman with MPD‐associated severe pruritus was successfully treated with danazol, as described in case study 1. Because pruritus repeatedly recurred upon withdrawal of danazol, she was unable to stop danazol; her MPD has been in complete remission for 18 years. The present study was motivated by our experience with that case.

A recent study showed that low doses of busulfan were able to decrease the number of individual stem/progenitor clones. After a single dose of busulfan, the majority of the same clones reappeared in a few months.24 Busulfan was successfully used in the management of anemia in patients with MPD.25^–27 Cytarabine and 6‐MP are nucleoside analogues and are widely used for the treatment of acute myeloid and lymphoid neoplasm in combination with other drugs.28 Sporadic reports in the literature document the efficacy of cytarabine and 6‐MP in MPD.29^–32

The E and G responders in this study were maintained in remission for many months on danazol alone, with significant reduction of blood counts and splenomegaly. This may suggest that danazol plays a role in controlling cell proliferation and extramedullary hematopoiesis, thereby maintaining remission for prolonged periods. However, the underlying mechanism of danazol in MPD remains to be elucidated.

For patients with advanced MPD, who had failed to most known measures, there are little options available except frequent transfusions and hospitalization. Most of our patients belonged to this group and were advised for hospice care. It is remarkable that some of these patients achieved hematological and clinical remission along with surprising improvement of their quality of life. They were able to resume their routine activity and enjoyed their lives over years.

In summary, danazol combined with intermittent chemotherapy with busulfan and occasionally other agents as described appears to be a safe and effective therapy in MPD. It is well tolerated with acceptable side effects; no serious complications were encountered. It induced long‐lasting remissions with improvement of blood counts and impressive reduction of spleen size, with concomitant elimination of systemic symptoms associated with splenomegaly, and drastic improvement of the performance status. Remissions were well maintained with danazol alone over years. It appears well suited for elderly patients with advanced MPD.

A larger scale prospective study is called to evaluate the true value and the indications of this regimen in patients with MPD, and to investigate the mechanism of action of danazol.

The present study was supported by a grant from the Wallace H Coulter Foundation and the Mary Beth Research Fund.