Effective management of accelerated phase myelofibrosis with low-dose splenic radiotherapy^†

The main cause of hepatosplenomegaly in primary (PMF), post polycythemia vera (post-PV MF), and post essential thrombocythemia (post-ET MF) myelofibrosis (MF) is extramedullary hematopoiesis (EMH). Drug-refractory symptomatic splenomegaly in MF is usually managed by splenectomy or involved-field radiotherapy. The latter is most effective in the treatment of MF-associated bone pain and pulmonary hypertension. Our previous experience with hepatosplenic radiotherapy in MF showed efficacy in the majority of treated patients but its utility was limited by the transient nature of its benefit and the occurrence of treatment-related pancytopenia. In an effort to address these issues, we have adopted an induction-maintenance treatment strategy that utilizes lower radiation doses—induction with 100 cGy total in four daily doses of 25 cGy and maintenance with either the same or lower intensity regimen. Herein, we report our most recent experience using this treatment plan in two cases, who in addition to their expected response from the standpoint of splenomegaly, also unexpectedly showed a marked response of their underlying accelerated phase disease, including clearance of circulating blasts and basophilia.

Case #1

AB is a 45-year-old male with post-PV MF (Table I). In October 2008, the patient was enrolled in a JAK1/2 inhibitor (INCB018424) clinical trial and at the time had massive splenomegaly (27 cm below left costal margin), 25 pound weight loss, and significant constitutional symptoms. He failed to exhibit a sustained response and the study medication was tapered with the intent to discontinue. During the taper, the patient experienced a systemic inflammatory response syndrome with multiorgan failure and pleural/pericardial effusions, which was effectively managed by readjusting the INCB018424 dose and instituting, in addition, high-dose corticosteroid and hydroxyurea therapy.

The patient continued to experience persistent/progressive hypercatabolic symptoms, leukocytosis/thrombocytosis, symptomatic splenomegaly, and circulating immature cells, and therefore, received three courses of intravenous cladribine therapy at 5 mg/m²/day × 5 days on 4/15/2009, 5/7/2009, and 7/17/2009. At the same time, his recurrent pleural effusion required repeated thoracentesis and treatment with lung radiation (100 cGy in 1 fraction on 6/11/2009). Because of progressive disease despite the aforementioned therapeutic measures, gemtuzumab-ozogamycin was administered without benefit.

Splenic radiotherapy at 100 cGy total dose in 4 daily fractions of 25 cGy was started on 9/15/2009, and improvement in dyspnea and early satiety commenced shortly afterward. The treatment was not associated with any significant decrease in blood counts, so the patient received a second course of splenic radiation starting 9/29/2009; he concurrently received 200 cGy in a single fraction to both legs for significant leg pain. Following this, he reported significant improvement in abdominal/leg pain (pain score from 9 to 4, on a scale of 0 to 10) such that he was able to begin ambulating, and also had near normalization of blood counts. He received a third course of splenic/leg radiotherapy at identical doses starting 10/27/2009, with full relief from abdominal/leg pain (spleen size 22 cm below left costal margin). In February 2010, he developed severe upper extremity pain and exhibited partial spleen regrowth; consequently he received a fourth course of splenic radiotherapy along with upper extremity radiation (200 cGy in single fraction) starting 2/22/2010.

Complete blood count before course #1 was: Hemoglobin (Hgb) 13.3 g/dL, white blood cell count (WBC) 22 × 10⁹/L with 19% blasts, and platelet count (Plt) 590 × 10⁹/L; before course #2: Hgb 13.6, WBC 20.8, Plt 572; before course #3: Hgb 14.2, WBC 6.1, Plt 160; and before course #4: Hgb 16.8, WBC 25.1, Plt 299. At last follow-up, the patient had marked improvement in his performance status such that he was ambulatory and able to return to work part-time. His blood counts had near normalized and he had complete resolution of peripheral blood leukoerythroblastosis included complete eradication of circulating blasts (Table I).

Case #2

TMB is a 42-year-old female, who was diagnosed with post-ET MF in June 2007, after 12 years of antecedent ET with an uncomplicated course (Table I). She had been followed expectantly without treatment with the exception of daily aspirin for thromboprophylaxis. In December 2009, she presented with subacute onset of an urticarial skin rash with progressive splenomegaly and leukocytosis, as well as with severe fatigue and marked abdominal discomfort. Her physical examination confirmed massive splenomegaly and the peripheral blood smear showed new onset eosinophilia and basophilia. A bone marrow biopsy confirmed post-ET MF without leukemic transformation, and molecular and cytogenetic studies were normal/negative.

The patient received splenic radiation (100 cGy in 4 daily fractions of 25 cGy each) starting on 12/18/2009 with rapid control of myeloproliferation (Table I). Before treatment, Hgb was 10.3 g/dL, WBC 134.6 × 10⁹/L, and Plt 115 × 10⁹/L. At 3 weeks following completion of radiotherapy, Hgb was 7.4 g/dL, WBC 1.0 × 10⁹/L, Plt 44 × 10⁹/L; at 4 weeks: Hgb 6.7 g/dL, WBC 1.3 × 10⁹/L, Plt 122 × 10⁹/L; and at 5 weeks: Hgb 7.2 g/dL, WBC 2.9 × 10⁹/L, Plt 150 × 10⁹/L. The patient was transfused with 8 units of red cells and 4 units of platelets over a 6 week period for pancytopenia at the discretion of her physicians. It is important to note that the patient was being tapered off hydroxyurea therapy in the first 3 weeks of radiotherapy. At her 6 week assessment, spleen volume (based on CT) had decreased from 7025 cc to 2741 cc (60% decrease). Since then, the patient has received maintenance radiotherapy (single fraction of 25 cGy to the spleen) every 5 weeks. At last follow-up, the patient was markedly improved with complete relief from abdominal pain (spleen volume 1757 cc) and near normal blood counts with complete resolution of peripheral eosinophilia/basophilia and marked decrease in leukoerythroblastosis (Table I). She was able to go back to workfull-time within 6 weeks of starting radiotherapy and start an exercise regimen.

Discussion

Radiotherapy is an attractive treatment option in both hepatosplenic and nonhepatosplenic EMH [1-3]. In a Mayo Clinic study of 23 MF patient undergoing splenic irradiation, a median dose of 2.8 Gy (range 0.3–14) was given in a median of 7.5 fractions (range 2–17) [4]. Approximately 94% of the patients achieved an objective response in spleen size and the median duration of response was 6 months. Approximately 44% of treated patients experienced treatment-related and sometimes life threatening cytopenia [4]. In another Mayo Clinic study [5], MF patients with (five patients) or without (nine patients) associated ascites received hepatic irradiation at a median dose of 1.5 Gy (range 0.5–10) given in a median of 6 fractions. Reduction in liver size was documented in 35% of the patients (median response duration was 3 months). Treatment-associated cytopenia occurred in the majority of the patients [6].

Leukemic transformation of myelofibrosis frequently occurs through an intermediate “accelerated” phase in its evolution from chronic phase of the disease. Although there is no uniform consensus definition for accelerated phase myelofibrosis at the present time, it is characterized by rapid clinical progression with survival less than a year; other characteristics that describe this phase include increased peripheral blood/bone marrow myeloblasts, thrombocytopenia, and possibly, specific cytogenetic abnormalities [7, 8]. Akin to accelerated phase of chronic myeloid leukemia, this phase of myelofibrosis is characterized by increasing refractoriness to conventional therapies, such as HU, and consequently represents a significant therapeutic challenge; the choice and intensity of therapy in this setting is generally determined on a case-by-case basis after consideration of patient and disease characteristics.

Although there are published reports of the efficacy of splenic radiotherapy in myelofibrosis patients, the current case report is unique in that it is restricted to patients with accelerated phase of the disease. We demonstrate the feasibility and efficacy of low-dose splenic radiotherapy utilizing a strategy of induction with 100 cGy in 4 daily 25 cGy fractions, followed by maintenance phase of intermittent radiotherapy at the same or lower dose (i.e., 25 cGy). The response to splenic radiotherapy was rapid in both cases, with decreased spleen size and WBC count becoming clearly evident within the first few weeks after radiotherapy; the treatment was extremely well tolerated with no evident extramedullary toxicity. Myelosuppression can ensue from splenic radiotherapy; for case #2, Grade 3 cytopenias were observed with induction radiotherapy, but not seen later during the maintenance phase; the cytopenias were likely related to concurrent HU therapy as well as the large initial radiation treatment field that covered the spine and pelvis. With subsequent discontinuation of HU and smaller treatment dose delivered via oblique fields that were tapered off at the bone marrow, myelosuppression did not recur. We believe the currently described treatment strategy, which represents a significant therapeutic advance that is worthy of being tested in a prospective fashion in larger group of patients with accelerated phase myelofibrosis.