Modern Management of Splenomegaly in Patients with Myelofibrosis

Abstract

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm which can lead to massive splenomegaly secondary to extramedullary hematopoiesis. Patients frequently exhibit debilitating symptoms including pain and early satiety, in addition to cellular sequestration causing severe cytopenias. JAK 1/2 inhibitors, such as ruxolitinib and fedratinib, are the mainstay of therapy and produce significant and durable reductions in spleen volume. However, many patients are not eligible for JAK 2 inhibitor therapy or become refractory to treatment over time. Novel therapies are in development that can reduce the degree of splenomegaly for some of these patients. However, splenectomy, splenic irradiation, and partial splenic artery embolization remain valuable therapeutic options in select patients. In this review, we will discuss currently available pharmacologic therapies and describe promising drugs currently in development. We will also delve into the efficacy and safety concerns of splenectomy, splenic irradiation, and partial splenic artery embolization. Finally, we will propose a treatment algorithm to help guide clinicians in the management of symptomatic splenomegaly in patients with MF.

Introduction

The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). These diseases are clinically characterized by constitutional symptoms, propensity for thrombosis, and to varying extent the development of splenomegaly.¹ While rarely present in ET, splenomegaly is commonly seen in about one third of patients with PV and even more frequently in MF.² Massive splenomegaly is particularly pervasive in patients with MF, with 38% of patients having a palpable spleen at least 10 centimeters (cm) below the left costal margin (LCM) and 23% with a spleen extending more than 16 cm.^3,4

Symptoms secondary to splenomegaly include pressure and pain in the left upper quadrant of the abdomen, pain in the left shoulder, and early satiety secondary to compression of the stomach. In addition, massive splenomegaly may lead to portal hypertension (and its associated sequalae) from high pressures being transmitted back to the portal system. Patients with MF can also have splanchnic vein thrombosis, hepatic extramedullary hematopoiesis (EMH), and obliterative portal venopathy.^5,6 Massive splenomegaly can also result in compression of the vena cava / iliac veins, resulting in lower extremity edema. In addition, cellular sequestration leading to exacerbation of existing cytopenias is common and can further limit medicinal options.⁷ In some cases, the extent of splenomegaly can lead to areas of ischemia resulting in painful splenic infarctions.⁸ The detrimental impact of splenomegaly on overall quality of life of patients with MF is reflected in a large patient survey which identified reduction in spleen size as one of the top five treatment goals.⁹ The presence and degree of splenomegaly has negative prognostic influence patients with ET/PV.¹⁰ The independent prognostic impact of splenomegaly has not been demonstrated in patients with MF, as many patients with splenomegaly also have well established adverse clinical variables such as abnormal karyotype, severe anemia, and constitutional symptoms.^11,12

Assessment of splenomegaly is routinely accomplished via manual palpation of the left upper abdominal quadrant with left coastal margin as the point of reference. If the spleen is nonpalpable, examination with the patient in the right lateral recumbent position may bring the spleen into a palpable position. Moderate-to-severe enlargements may be documented on physical exam, while more subtle splenomegaly requires imaging for accurate assessment.^13,14 The mean splenic volume of healthy volunteers is 166 cm³ with a mean length 10.9 cm. Typically, a spleen length greater than 12 cm on imaging is considered enlarged, although factors such as height and gender must be taken into account.¹⁵ The utility of imaging is primarily to document objective responses to therapy during a clinical trial, although routine clinical use may be appropriate for patients with a body habitus which precludes palpation. Ultrasound is the most widely validated, however there are limitation to its accuracy, most notably interoperator variability. Therefore, magnetic resonance imaging (MRI) has emerged as a technique to objectively measure spleen volume, particularly in the clinical trial setting.¹⁶

The mainstay of pharmacologic-induced spleen reduction in MF is the use of JAK 1/2 inhibitors, such as ruxolitinib (Jakafi, Incyte) and recently approved fedratinib (Inrebic, Celgene/BMS). These oral small molecular inhibitors have proven efficacy in ameliorating splenomegaly and have fundamentally changed the approach to addressing splenomegaly in MF.^17–20 However, roughly 15% of patients are not eligible for JAK 2 inhibitor therapy given thrombocytopenia below 50 × 10⁹/L.²¹ In addition, many patients become refractory to JAK 2 inhibitors. Based on follow up from the COMFORT studies, the discontinuation rate for ruxolitinib therapy is 50% at 3 years and 72.8% at 5 years.^22,23 Furthermore, patients who progress on ruxolitinib have a dismal survival of only 14 months.²⁴ Therefore, other modalities are often explored to treat symptomatic splenomegaly in patients with MF.

In this review, we will first describe the pathophysiology of splenomegaly in MPNs. We will then describe the benefits, and limitations, of JAK 2 inhibitor therapy for the treatment of splenomegaly. We will then briefly describe novel therapies that are being developed to address splenomegaly in MF. Direct modalities, such as splenectomy, partial splenic artery embolization, and splenic irradiation will be considered. Finally, we will propose a treatment algorithm for the optimal management of symptomatic splenomegaly in patients with MPNs in the modern era.

Anatomy and Pathophysiology

The spleen is organized into two distinct compartments, the white pulp and red pulp. The white pulp serves as a lymphocyte reservoir while the red pulp functions to filter blood.²⁵ The red pulp is organized into a loose reticular network of capillaries and sinuses. Littoral cells (LCs) line the sinus walls and serve as filters for red blood cells, while splenic vascular endothelial cells (SVECs) line the capillary walls.^26,27 These cells have distinct cellular functions, with LCs functioning as cellular filters and scavengers.²⁸ The spleen is encapsulated in dense fibrous tissue and smooth muscle tissue. Blood enters via the splenic artery, which branches into smaller arterioles, As much as 90% of total splenic blood flows through venous sinuses, bypassing the filtration system of the red pulp.²⁹ Blood exits via the splenic vein which then combines with the superior mesenteric vein to become the portal vein.

The splenomegaly in MPNs is primarily due to EMH. Abnormal trafficking of hematopoietic stem cells (HSC) due to a highly-dysregulated bone marrow microenvironment leads to engraftment in extramedullary sites such as the spleen.³⁰ The splenic niche is likely composed of several components that lead to expansion of the hematopoietic space. Stem cell factor (SCF), an important cytokine in hematopoietic development, is expressed by endothelial cells and stromal cells in the sinusoids in the red pulp of the spleen.³¹ In MF patients, the capillary, but not sinusoidal, vascular density is increased.³² LC density is decreased in MF while SVECs demonstrate activated interferon signaling, cell cycle progression, and increased vascular endothelial growth factor receptor expression. MF SVECs promote the generation of a greater number of HSC progenitors as compared with normal SVECs in vitro.²⁷ In addition, the C-X-C motif chemokine ligand 12 (CXCL12), also called stromal-derived factor 1 (SDF-1), is normally produced by osteoblasts in the bone marrow and leads to development and maintenance of the HSC. CXCL12 and its receptor CXCR4 are key mediators of HSC trafficking and alterations in this regulatory axis leads to abnormal HSC migration in MF patients and murine models of MF.³³ Importantly, CXCL12 is also produced by endothelial cells in the splenic red pulp of patients with EMH.^31,34,35 Patients with PV and MF also have increased amounts of truncated CXCL12, which lacks the ability of HSCs to localize to the bone marrow leading to profound mobilization of HSCs into the peripheral blood and their eventual migration to the spleen.³⁶

Interestingly, activation of JAK-STAT signaling, which is central to the pathophysiology of MPNs, promotes CXCL12 signaling and induces CXCL12-dependent HSC migration and the downstream activation of the STAT, PI3K/AKT, and RAS/MAPK pathways. Inhibition of the JAK-STAT pathway with ruxolitinib leads to decreased chemotaxis in an in vitro model.³⁷ Not surprisingly, the presence of the JAK2V617F mutation is an independent predictor of progressive splenomegaly.³⁸ Another pathophysiologic mechanism leading to splenomegaly in MF is provided by studies of the GATA1 mouse model. GATA1 is a transcription factor important for erythroid and megakaryocytic differentiation. GATA1-deficient mice lack expression of the CXCL12 receptor CXCR4 but still develop EMH, suggesting that a CXCL12- independent pathway also contributes to the development of splenomegaly.^33,39

Conventional cytoreductive therapies

For patients with symptomatic splenomegaly, there are a number of therapies available with demonstrated efficacy in reducing splenomegaly. Prior to the advent of JAK 2 inhibitors, several agents were explored as spleen reducing therapies in MF. Hydroxyurea is an oral ribonucleotide reductase inhibitor which is frequently employed as front line cytoreductive therapy in PV and ET. In patients with MF, hydroxyurea is typically reserved for patients who have hyperproliferative features including splenomegaly, leukocytosis, and constitutional symptoms that are not eligible for JAK 2 inhibitors. In a report of 40 MF patients with proliferative features, hydroxyurea treatment was associated with a spleen response rate of 40%. However, there were toxicities including dose-limiting cytopenias which occurred in 18 patients (45%). In addition, oral and lower extremity skin ulcers occurred in 5 patients (12.5%).⁴⁰

Other cytoreductive therapies used in the treatment of MF are either ineffective in reducing spleen size or are associated with unacceptable toxicities. Interferon alfa therapy has been evaluated but limited minimal spleen responses have been observed.⁴¹ Low-dose melphalan is moderately effective in reducing splenomegaly, but can lead to the emergence of significant cytopenias, and may predispose to leukemic transformation.⁴² The immunomodulatory drugs thalidomide and lenalidomide have been extensively evaluated in MF, and while they have demonstrated ability to improve anemia in a subset of treated patients, spleen responses are modest ranging from 10–20%.^43,44

JAK 1/2 Inhibitors

The most effective pharmacologic tool for reducing splenomegaly in MF is JAK2 inhibition. The mechanism behind spleen reduction with JAK2 inhibitors is not well understood, although this may be related to inhibition of JAK2 mediated HSC migration via the CXCL12/CXCR4 pathway.³⁷ Ruxolitinib is a JAK 1/2 inhibitor which was Food and Drug Administration (FDA)-approved in 2011 for the treatment of intermediate and high-risk MF and later gained approval for the treatment of PV not responsive or intolerant to hydroxyurea.⁴⁵ Approval in MF was based on the pivotal COMFORT studies. These two phase III trials randomized MF patients with intermediate- or high-risk disease involved randomization to ruxolitinib versus placebo in COMFORT I, or versus best available therapy (BAT) in COMFORT II. Both studies established the efficacy of ruxolitinib in improving standardized symptom scores after 24 weeks.^17,18

In COMFORT I, ruxolitinib led to a mean reduction in spleen volume of 31.6% at week 24 compared with a mean increase of 8.5% in the placebo arm. The primary endpoint of ≥35% spleen volume reduction (SVR_35%) was achieved in 41.9% of the ruxolitinib treatment arm as compared with 0.7% of the placebo treatment arm.¹⁷ This reduction was also durable with a mean duration of response of 168.3 weeks with long-term follow up.⁴⁶ Similar results were observed in the COMFORT II study where there was a mean decrease of 29.2% at 24 weeks in the ruxoltinib group as compared to an increase of 2.7% in the BAT group. SVR_35% was achieved in 32% of the ruxolitinib-treated patients as compared with 0% of the BAT-treated patients.¹⁸ After 5 years, 53.4% of patients who received ruxolitinib eventually met the SVR_35% endpoint with a mean duration of 3.2 years.⁴⁷ In both studies, improvement in splenomegaly was seen within 1 month of initiation of ruxolitinib, and over time there was further improvement in splenomegaly over 48 weeks of follow-up. Anemia and thrombocytopenia, the primary treatment emergent adverse events associated with ruxolitinib therapy, are often manageable but can frequently lead to treatment discontinuation.^17,18 Importantly, the degree of spleen response with ruxolitinib is dose-dependent, with higher doses achieving more significant spleen responses.⁴⁸ Post-hoc pooled analysis of the COMFORT studies suggest that patients who had a spleen volume reduction (SVR) of at least 25% had a prolonged survival as compared to patients without a spleen reduction or with an increase.⁴⁹ Ruxolitinib may also improve portal hypertension via reduction in splenic arterial flow and direct vasodilatory effect on the intrahepatic sinusoids. One report demonstrated normalization of sinusoidal portal hypertension after 42 months of ruxolitinib.⁵⁰

While the initial response rate to ruxolitinib therapy is high, patients eventually develop intolerance or progressive splenomegaly. Long term follow-up from COMFORT I and II showed that at 3 years, approximately 50% of patients were no longer receiving ruxolitinib therapy.²³ The prognosis for patients who discontinue ruxolitinib is dismal, with one study reporting a median OS of only 14 months.²⁴ Patients who are refractory to ruxolitinib should be evaluated for alternative clinical trials if available. Recently, another JAK2 inhibitor has gained FDA approval.⁵¹ Fedratinib is a potent JAK2 inhibitor which has been evaluated in the front line setting in the JAKARTA study, which randomized MF patients to placebo, fedratinib at 400mg or fedratinib at 500mg once daily. Similar to the COMFORT I study, there was a significant improvement in SVR_35% in the fedratinib treatment arms as compared to the placebo arm. Specifically, patients in the fedratinib arms attained SVR_35% of 36% and 40%, respectively, versus only 1% in the placebo arm. Almost all patients attained a degree of spleen reduction, as can be appreciated in the SVR waterfall plots.¹⁹

Fedratinib has also been evaluated in the second line setting in patients who are refractory or intolerant to ruxolitinib after at least 14 days of therapy. In the single-arm, open label phase 2 JAKARTA-2 study, 97 patients with intermediate or high-risk MF were treated with fedratinib 400mg daily. Of these 97 patients, 66% were ruxolitinib-resistant and 33% were ruxolitinib-intolerant as defined by the investigator, most commonly secondary to ruxolitinib-induced hematologic toxicity. Of the 83 patients with information available for assessment at 24 weeks, 55% achieved SVR_35% as measured by imaging. Twenty-nine (53%) of the 55 patients resistant to ruxolitinib and 17 (63%) of 27 patients intolerant to ruxolitinib achieved spleen responses at 24 weeks. The median decrease in spleen volume was 34%.¹⁹

Unfortunately, there are limitations to effective dosing for both approved JAK inhibitors, including treatment-emergent hematologic toxicities, in particular dose-limiting thrombocytopenia. In addition, anemia is a common on-target treatment-related adverse event. Therefore, investigational JAK inhibitors are being developed to meet the unmet need of MF patients with anemia and thrombocytopenia.

Momelotinib (Sierra Oncology) is a selective inhibitor of JAK1, JAK2, and ACVR1 which has been evaluated in two phase III trials. The SIMPLIFY-1 trial randomized 432 JAK 2 inhibitor-naïve MF patients with palpable splenomegaly to momelotinib or ruxolitinib. This trial demonstrated non-inferiority of momelotinib for SVR_35% at 24 weeks (26.5% with momelotinib and 29% with ruxolitinib); the study failed to meet non-inferiority criteria for symptom response. However, more patients were transfusion-independent at week 24 in the momelotinib arm as compared with ruxolitinib.⁵² Momelotinib was also evaluated in MF patients after ruxolitinib failure. In the SIMPLIFY-2 study, 156 patients who were intolerant or refractory to ruxolitinib were randomized 2:1 to momelotinib or BAT. There was no significant difference in SVR_35% between the two arms (7% in the momelotinib arm and 6% in BAT).⁵³ The low response rates seen in both arms of SIMPLIFY-2 are likely related to the trial design, which lacked a ruxolitinib wash-out period before trial entry. Clinical development of momelotinib is currently focused on anemic MF patients in the ongoing phase 3 MOMENTUM study (NCT04173494).

Another JAK 2 inhibitor in development is pacritinib (CTI Biopharma), which has been evaluated in two large phase III trials. In the PERSIST-1 trial, MF patients without prior JAK inhibitor exposure and irrespective of baseline platelet count were randomized 2:1 to pacritinib or BAT. SVR_35% was achieved in 19% of patients in the pacritinib group versus 5% in the BAT group. Importantly, pacritinib achieved SVR_35% in 23% of patients with platelet count less than 50 × 10⁹/L, compared to 0% in the BAT group.⁵⁴ In PERSIST-2, MF patients with baseline thrombocytopenia (<100 × 10⁹/L) irrespective of prior ruxolitinib therapy were randomized 1:1:1 to pacritinib 400mg daily, pacritinib 200mg BID, or BAT including ruxolitinib. Similar to PERSIST-1, the SVR endpoint was achieved in significantly more patients as compared with BAT (18% in the combined pacritinib arms versus 3% in the BAT arm). There was also significant activity in MF patients with a platelet count less than 50 × 10⁹/L as compared with the BAT group. Importantly, in the subgroup of patients with platelets less than 50 × 10⁹/L, SVR_35% was achieved in 18% and 29% of the patients in the pacritinib 400mg daily and 200mg cohorts, as compared with 3% of the BAT group.⁵⁵ Notably, a full clinical hold was placed on pacritinib development during the PERSIST-1 and PERSIST-2 trials due to adverse events including bleeding, cardiovascular events and death observed at an early timepoint in PERSIST-1, resulting in the early termination of these trials. Upon final review of data, however, this clinical hold was lifted and a dose-finding trial, PAC203, was conducted in patients who had failed ruxolitinib. This trial demonstrated that 200mg BID was the most effective dose resulting in SVR_35% rates of 9.3% in this previously JAK inhibitor-treated population.⁵⁶ Given promising activity of pacritinib in thrombocytopenic patients, a phase III trial, PACIFICA, is currently accruing MF patients with a platelet count less than 50 × 10⁹/L (NCT03165734).

While JAK2 inhibitors have fundamentally changed the pharmacologic management of splenomegaly in MF, patients eventually become refractory to these agents. Importantly, these therapies do not appear to significantly impact the natural course of MF. One must remember that MF is a disease involving a malignant HSC that is not affected by JAK2 inhibitor therapy.^57,58 One must be acutely aware that spleen reduction is an important but limited therapeutic goal. Furthermore, Kremyanskaya et al first demonstrated that evolution to MPN blast phase can occur in patients receiving ruxolitinib and that progression to this uniformly fatal stage of the disease is not affected by JAK2 inhibitor therapy at present.⁵⁹ Therefore, novel agents are urgently needed to address symptomatic splenomegaly and to prolong the lives of patients with MF.

Novel Therapies

With increasing knowledge of the pathobiologic basis of MF, multiple new therapies are in clinical development which appear to address symptomatic splenomegaly in addition to providing symptom relief and improve quality of life (Table 1).

Table 1.

Pharmacologic Therapies

	Mechanism of Action	Number of evaluable patients	Ruxolitinib Exposure	Spleen volume results
FDA Approved
Ruxolitinib	JAK 1/2 inhibitor	155, 146	N/A	32–42% SVR35% 24 weeks
Fedratinib	JAK 2/FLT3 inhibitor	193	Ruxolitinib naïve	36–40% SVR35% at 24 weeks
		97	Ruxolitinib intolerant/refractory	55% SVR35% at 24 weeks
Investigational Single Agents
Momelotinib	JAK 1/JAK 2/ACVR1 inhibitor	215	Ruxolitinib naïve	26.5% SVR35% at 24 weeks
		104	Ruxolitinib intolerant/refractory	7% SVR35% at 24 weeks
Pacritinib	JAK 2/FLT3/IRAK1 inhibitor	220	Ruxolitinib naïve	19% SVR35% at 24 weeks
		211	Ruxolitinib naïve or previously treated	18% SVR35% at 24 weeks
Investigational Combinations
Thalidomide + Ruxolitinib	Immunomodulatory	11	Inadequate response to ruxolitinib	54.5% SVR35% at 12 weeks
Navitoclax + Ruxolitinib	BCL-2/BCL-xL inhibitor	24	Inadequate response to ruxolitinib	29% SVR35% at 24 weeks
CPI-0610+ Ruxolitinib	BET inhibitor	31	Inadequate response to ruxolitinib	94% had spleen reduction 17% average spleen reduction
		15	Ruxolitinib naïve	80% SVR35% at 24 weeks
Pegylated interferon 2-alpha + Ruxolitinib	antiproliferative, proapoptotic, immunomodulatory	4	Ruxolitinib naïve	10% reduction in SVR at 2 years*

IWG-MRT = International Working Group-Myeloproliferative Neoplasms Research and Treatment; N/A = not applicable; SVR_35% = spleen volume reduction of at least 35%

^*In overall cohort including PV patients. In MF patients with splenomegaly, outcome not reported. Reduction was not statistically significant for MF patients at 6 months or afterwards.

A promising agent in clinical developing is the oral bromodomain and extra-terminal domain (BET) inhibitor CPI-0610 (Constellation Pharmaceuticals), which has demonstrated clinical activity in patients with MF. The BET family of proteins modify multiple epigenetic pathways impacting gene expression. In a murine model, BET inhibitors dampen NF-κB pathway activity with reduction in splenomegaly.⁶⁰ In a phase 2 trial of CPI-0610, patients either refractory/intolerant to ruxolitinib or with an inadequate response were administered CPI-0610 monotherapy or CPI-0610 in combination with ruxolitinib. In the combination therapy cohort, 29 (94%) of the 31 evaluable patients attained some degree of reduction in spleen volume, with a mean reduction of 17% from baseline.⁶¹ CPI-0610 was also active in the up-front setting, with 12 of 15 (80%) JAK inhibitor-naïve patients attaining SVR_35% based on preliminary data.⁶² Mature follow up is eagerly awaited for this promising therapy.

Several agents are also being investigated in combination with ruxolitinib. Navitoclax (AbbVie) is a BCL-2/BCL-xL inhibitor which has been evaluated in combination with ruxolitinib in MF patients who had an inadequate response to single agent ruxolitinib. Seven of the 24 (29%) evaluable patients treated with combination therapy achieved SVR_35% by imaging at week 24 and 42% of patients achieved this reduction at any time while on trial.⁶³ Another combination therapy approach under active investigation is the immunomodulatory agent thalidomide and ruxolitinib. A phase 2 study including 23 patients who were either ruxolitinib-naïve or had an inadequate response demonstrated any degree of SVR in 6 of 11 evaluable patients (54.5%). Importantly, there was an increase in platelet count in 75% of patients.⁶⁴ Finally a phase II study has been performed evaluating ruxolitinib in combination with pegylated interferon alfa-2a (Pegasys, Genentech), in which 18 patients with MF were treated with weekly pegylated interferon alfa-2a at a subcutaneous dose of 45 μg in combination with ruxolitinib dosed based on platelet count. In the overall cohort, spleen size was significantly decreased. At 2 years there was a 10% decrease in spleen size. However, this reduction was not statistically significant in the 4 MF patients with baseline splenomegaly. Of note, this cohort treated with combination ruxolitinib and pegylated interferon alfa-2a were early stage, with 83% either low or intermediate-1 risk by the Dynamic International Prognostic Scoring System.⁶⁵

Additional novel therapeutics are in development with attention towards patients who have relapsed or are refractory to JAK2 inhibitors. Despite promising pharmacologic options on the horizon, many patients are ineligible for clinical trials or have progressed with limited treatment options. These patients should be evaluated for other, more invasive modalities.

Splenectomy

Prior to the advent of JAK 2 inhibitor therapy, splenectomy was commonly performed to palliate spleen-related symptoms. In addition, surgical splenectomy can be utilized to improve anemia and thrombocytopenia by allowing for sequestered blood cells to enter the peripheral circulation. In a study that predates the development of ruxolitinib, splenectomy was performed in 314 MF patients for the stated reasons of mechanical symptoms (49%), anemia (25%), portal hypertension (15%), and thrombocytopenia (11%). The procedure was associated with significant perioperative complications in 87 patients (27.7%), including infection (9.9%), thrombosis (9.9%) and bleeding (14%). In this study, long-term symptomatic improvement occurred in 121 out of 156 patients (77.6%). The overall survival was 19 months post-splenectomy.⁶⁶ While for many indications laparoscopic splenectomy is the preferred surgical approach,⁶⁷ in patients with massive splenomegaly laparoscopic splenectomy is not technically feasible, and the procedures are typically performed open.

Many clinicians advocate for splenectomy prior to allogeneic hematopoietic stem cell transplantation in order to improve engraftment. The benefits of this strategy remain an area of debate. A prospective study from the European Society for Blood and Marrow Transplantation has demonstrated a trend towards faster leukocyte recovery time (16 days versus 18 days) with splenectomy but with a significantly higher relapse rate (51% versus 20%). There was no impact on overall survival.⁶⁸ However, in a recent single center study, patients with pre-transplant splenectomy had no difference in post-transplant relapse but did have an improved overall survival.⁶⁹

In the present day, splenectomy is still a valuable therapeutic strategy in patients who are refractory, intolerant to, or ineligible for JAK 1/2 inhibition, ineligible for a clinical trial, and have massive and symptomatic splenomegaly. However, careful patient selection is key. In one study including 15 patients with MPNs, presence of more than 2 comorbidities and American Society of Anesthesiologist fitness grade greater than 2 (indicating disease that impacts activity) were associated with a greater number of postoperative complications.⁷⁰ In addition, hematologic parameters are important, as highlighted by a series of 12 MPN patients where postoperative mortality was significantly higher in patients with a platelet count of less than 20 × 10⁹/L. In this series, 6 patients (50%) experienced post-operative bleeding and 5 patients (41.7%) had an abscess or infection. One patient (8.3%) died of respiratory failure in the post-operative setting.⁷ Of note, it important to reinstitute JAK 2 inhibitor therapy post-splenectomy if possible to prevent accelerated hepatomegaly from EMH in the liver.

Concerns of accelerating leukemic transformation in MF after splenectomy have also be raised. One single-center retrospective study during the pre-ruxolitinib era suggested that splenectomy during disease evolution (bone marrow blasts ≥ 10%) was associated with inferior overall survival.⁷¹ In a separate study of 233 MF patients in the pre-ruxolitinib era, blast transformation occurred in 16.3% and was increased further in the presence of pre-splenectomy thrombocytopenia. However, there was no difference in survival between patients who had blast transformation post-splenectomy and those who did not.⁷² A number of studies have found that splenectomy is associated with decreased survival as compared with MF patients who have not received a splenectomy.⁷¹ but these findings are very likely confounded by selection bias of patients who undergo splenectomy. Regardless, these concerns do not undermine the palliative role of surgical splenectomy in appropriately selected cases. In the present day, splenectomy should be performed at centers with expertise and experience given the complicated nature of this procedure in MF patients.

Prior to splenectomy, vaccinations must be administered for Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis as asplenism increases the risk of life-threatening infections from encapsulated organisms. Ideally, vaccinations should begin at least 10 weeks prior to splenectomy, although an adequate immune response occurs within 2 weeks if a more urgent splenectomy is required.⁷³

Splenic irradiation

In patients who are not surgical candidates because of poor performance status, splenic irradiation may be an option. The spleen is very radiosensitive, which allows a low dose to be effective. In addition, patients who have ascites secondary to EMH can also be treated with splenic irradiation. Many regimens have been utilized, however the most common is 10 Gy in 10 fractions based on meta-analysis data.⁷⁴ In a study of 23 patients with MF who were treated with 50 courses of splenic irradiation prior to the availability of ruxolitinib, 93.9% of the courses resulted in an objective response on physical exam. The median duration of response was 6 months (range 1–41 months). In additional, all patients experienced symptomatic improvement after splenic irradiation. Eight patients underwent multiple courses of splenic irradiation, and all patients continued to maintain responses.⁷⁵ This approach may even be effective in accelerated forms of MF.⁷⁶ The use of splenic irradiation in preparation for allogeneic hematopoietic stem cell transplantation is safe and effective, although it does not appear to improve overall survival in one retrospective series.⁷⁷

However, there are many complications of splenic irradiation. Most notably, significant myelosuppression occurs which can frequently result in worsening of disease-related anemia and thrombocytopenia and the development of neutropenia. Severe and prolonged cytopenias were reported in 26% of treated patients in the previously-mentioned series and resulted in fatal bleeding or sepsis in 3/23 (16%) patients.⁷⁵ Additionally, significant gastrointestinal toxicities including nausea and diarrhea can further complicate the clinical picture. However, for patients who have exhausted JAK 2 inhibitor options, are not eligible for clinical trials, and are not surgical candidates, splenic irradiation remains a potential therapeutic option for symptomatic splenomegaly.

Partial Splenic Artery Embolization

Total splenic artery embolization for the treatment of massive splenomegaly was first developed in the 1970s as a noninvasive treatment for massive splenomegaly.⁷⁸ However this procedure was associated with significant complications including splenic rupture, splenic abscess, sepsis, and death. Therefore, partial splenic artery embolization (PSE) incorporating antibiotic prophylaxis has been employed with significantly less complications. In addition, there is preservation of splenic tissue, which may preserve splenic function.⁷⁹ In a randomized trial of splenectomy versus PSE in patients with cirrhosis and splenomegaly, PSE resulted in a shorter hospitalization duration, less frequent transfusions, and less procedural pain as compared to splenectomy patients.⁸⁰ Modern techniques involve isolation of the splenic artery with preliminary angiogram followed by controlled embolization via microspheres, absorbable gelatin sponge, coils, vascular plugs, or liquid embolic agents such as ethyl vinyl alcohol (EvOH) or N-butyl-2 cyanoacrylate (NBCA).

PSE was initially employed in cirrhotic patients who were poor surgical candidates and later utilized in cases of traumatic splenic injury to prevent further bleeding.⁸¹ However, there is a paucity of available literature on the role of PSE in patients with MF. In a modern single-center experience of 35 cancer patients who underwent PSE using tris-acryl gelatin microspheres, 3 of these patients had MF. The overall group had a rapid and prolonged increase in platelet count, from a median of 65.7 × 10⁹/L pre-procedure to a peak platelet count of 221 × 10⁹/L two weeks after PSE.⁸² There is also a case report of 2 MF patients who had PSE to prepare for safe surgical removal during splenectomy, with favorable results.⁸³

In practice, the primary limitation of PSE is post-embolization syndrome, characterized by severe left upper quadrant pain often requiring intravenous pain control, hydration and hospitalization. This complication occurs in approximately 75% of treated patients, according to one prospective trial of PSE in cirrhotic patients.⁸⁴ This rate may be lower with newer embolic agents such as EvOH, although this is not well studied.⁸⁵ In addition, major complications such as splenic abscess, portal vein thrombosis, pleural effusions, and worsening ascites can also occur. These major complications occurred in 20% of cirrhotic patients according to one meta-analysis with an associated mortality rate of 2.3%.⁸⁶

PSE is currently employed in select MF patients who are not surgical candidates, who are deemed able to tolerate recovery from postembolization syndrome, and most importantly are treated at a center with expertise with this procedure.

Conclusions and Recommendations

Symptomatic splenomegaly remains a challenging clinical scenario in the care of patients with MF. Despite the advent of JAK2 inhibitors, many patients are either intolerant or eventually develop JAK 2 inhibitor refractory disease requiring alternative therapeutic approaches. Novel medical therapies are currently in development which may address splenomegaly in a proportion of patients who either do not achieve or lose an initial spleen response with JAK2 inhibitor treatment. Despite the improvement in pharmacologic management, however, splenectomy, splenic irradiation, and PSE remain important therapeutic tools to consider in the management of MF related splenomegaly.

Based on our experience, we have developed a clinical algorithm for the treatment of symptomatic splenomegaly in MF (Figure 1). This decision tree encourages participation in clinical trials given current limited pharmacologic options. Patients who are eligible for JAK2 inhibition (i.e. have adequate platelet counts) should first be treated with one of the commercially available agents, either ruxolitinib or fedratinib. Patients who are not candidates for a first-line JAK2 inhibitor or have failed JAK2 inhibition (one or more agents) should be evaluated for clinical trial enrollment. In patients who are not eligible for clinical trials, surgical splenectomy is our first choice given its demonstrated efficacy and safety. Patients who are not surgical candidates (poor performance status or competing comorbid conditions) should be considered for splenic irradiation or PSE, depending on provider, institutional, and patient preferences while balancing expectations and potential associated toxicities. For instance, in a patient who may be severely limited by postembolization syndrome (e.g., with advanced age or significant debility) we would recommend pursuing splenic irradiation. However, a patient who already has extreme cytopenias may be more appropriate for PSE.

Figure 1. Treatment algorithm for myelofibrosis patients with splenomegaly.

A practical treatment algorithm for the management of splenomegaly in myelofibrosis. While ruxolitinib and fedratinib should be employed upfront, whenever possible patients should be evaluated for clinical trial enrollment. Surgical splenectomy is the preferred approach in patients who have debilitating symptoms and are surgical candidates, while splenic irradiation and partial splenic artery embolization rely on patient specific considerations and provider preferences.

In summary, the modern management of splenomegaly in MF has fundamentally changed over the last decade and continues to evolve rapidly. Pharmacologic options are expanding including agents other than JAK2 inhibitors. For many patients, splenectomy, splenic irradiation, and PSE will remain valuable second-line treatment options. Ongoing research efforts are focused on the development of novel therapeutics that potently delete the malignant hematopoietic stem cells and result in restoration of normal hematopoiesis, with the elimination of EMH driving splenomegaly and ultimately prolonging life.