Splenic irradiation for myelofibrosis prior to hematopoietic cell transplantation: A global collaborative analysis.

Splenomegaly is the clinical hallmark of myelofibrosis. Splenomegaly at the time of allogeneic hematopoietic cell transplantation (HCT) is associated with graft failure and poor graft function. Strategies to reduce spleen size before HCT especially after failure to Janus kinase (JAK) inhibition represent unmet clinical needs in the field. Here, we leveraged a global collaboration to investigate the safety and efficacy of splenic irradiation as part of the HCT platform for patients with myelofibrosis. We included 59 patients, receiving irradiation within a median of 2 weeks (range, 0.9-12 weeks) before HCT. Overall, the median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48%-76%) and 1-year non-relapse mortality was 26% (95% CI, 14%-38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse (p = .01), showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy. In conclusion, splenic irradiation immediately before HCT is a reasonable approach in patients experiencing JAK inhibition failure and is associated with a low incidence of relapse.

Splenic irradiation for splenomegaly: A systematic review.

Splenic irradiation (SI) is a palliative treatment option for symptomatic splenomegaly (i.e. for pain, early satiety, pancytopenia from sequestration) secondary to hematologic malignancies and disorders. The purpose of the current article is to review the literature on SI for hematologic malignancies and disorders, including: (1) patient selection and optimal technique; (2) efficacy of SI; and (3) toxicities of SI. PICOS/PRISMA methods are used to select 27 articles including 766 courses of SI for 486 patients from 1960 to 2016. The most common cancers treated included chronic lymphocytic leukemia and myeloproliferative disorders; the most common regimen was 10Gy in 1Gy fractions over two weeks, and 27% of patients received retreatment. A partial or complete response (for symptoms, lab abnormalities) was obtained in 85-90% of treated patients, and 30% were retreated within 6-12months. There was no correlation between biologically equivalent dose of radiation therapy and response duration, pain relief, spleen reduction, or cytopenia improvement (r2 all <0.4); therefore, lower doses (e.g. 5Gy in 5 fractions) may be as effective as higher doses. Grade 3-4 toxicity (typically leukopenia, infection) was noted in 22% of courses, with grade 5 toxicity in 0.7% of courses. All grade 5 toxicities were due to either thrombocytopenia with hemorrhage or leukopenia with sepsis (or a combination of both); they were sequelae of cancer and not directly caused by SI. In summary, SI is generally a safe and efficacious method for treating patients with symptomatic splenomegaly.

Splenic irradiation provides transient palliation for symptomatic splenomegaly associated with primary myelofibrosis: a report on 14 patients.

We retrospectively analyzed the outcomes of 14 patients with primary myelofibrosis who were treated with splenic irradiation (SI) for symptomatic splenomegaly between January 2000 and December 2012 at 12 hospitals. Median age at the time of SI was 67 years (range 47-76). The median dose of radiation per course was 5 Gy, administered in a median of eight fractions. Spleen size was reduced in 93 % of patients, and persisted for a median of 2.2 months (range 0.1-13.8). Symptom relief occurred in 86 % of patients, and lasted for a median of 2.5 months (range 0.1-16.5). Although SI provided a high rate of palliation for patients with symptomatic splenomegaly, the responses were transient. Significant thrombopenia (<25 × 10(9)/L) occurred in eight patients (57 %), and neutropenia (<0.5 × 10(9)/L) was observed in seven (50 %). Nine patients (64 %) required an increased number of red blood cell transfusions after SI. Five patients (36 %) developed serious infections, with two deaths (14 %), as a result of SI-induced cytopenia. The median survival for all patients after SI was 18.5 months (range 0.1-71.9). The Dynamic International Prognostic Scoring System model effectively distinguished the prognosis after SI between patients in the intermediate-2 and high-risk groups.

Splenic irradiation as palliative treatment for symptomatic splenomegaly due to secondary myelofibrosis: a multi-institutional experience.

PURPOSE: To evaluate the impact of splenic irradiation as a palliative treatment for symptomatic splenomegaly due to secondary myelofibrosis. METHODS: Seventeen patients with chronic myelogenous leukemia and 3 with idiopathic polycythaemia presented with splenomegaly, splenic pain and anemia. Due to symptomatic splenomegaly, despite first-line treatment, the patients underwent splenic irradiation. Two patients received two different schedules of external radiotherapy (580 cGy in 5 fractions and 600 cGy in 6 fractions). Eight patients received 980 cGy in 14 fractions. Ten patients received two courses of 360 cGy in 6 fractions, 3 months apart. Median follow-up was 12 months post irradiation. RESULTS: The patients showed excellent response to treatment one month post-radiotherapy, while treatment was well tolerated without severe toxicity. The dimensions of the spleen decreased significantly. Pain-related Visual Analogue Score (VAS) regressed after completion of irradiation. During 12-month follow-up all patients maintained the benefit of radiotherapy. CONCLUSION: This study indicates that splenic irradiation could be a safe and effective palliative treatment for symptomatic splenomegaly due to secondary myelofibrosis.

Adaptive splenic radiotherapy for symptomatic splenomegaly management in myeloproliferative disorders.

AIMS AND BACKGROUND: Symptomatic, massive splenomegaly is a debilitating complication of myeloproliferative disorders. In the study, we evaluated the use of a contemporary, individualized radiotherapeutic approach for splenic irradiation, including 3-dimensional computed tomography-based treatment planning, individualized treatment margins based on splenic motion assessment, online setup verification with volumetric image guidance at each fraction, and adaptive radiation treatment planning to account for changes in splenic size during the fractionated radiotherapy course. METHODS AND STUDY DESIGN: Between December 2008 and January 2014, 18 patients (13 males, 5 females) with myeloproliferative disorders referred to Gulhane Military Medical Academy Radiation Oncology Department underwent 22 courses of splenic irradiation using 3-dimensional computed tomography-based treatment planning and volumetric image guidance for palliation of symptomatic splenomegaly. RESULTS: Median age was 64 years (range 28-79). Significant pain relief was achieved in 20 of the 22 splenic irradiation courses (90.9%). Improvement in hematological parameters was achieved in 8 of the 11 splenic irradiation courses applied for cytopenia (72.7%). At least a 50% reduction in splenic size was achieved in 18 of the 22 splenic irradiation courses (81.8%). Toxicity was manageable with supportive treatment including antiemetics and platelet or red blood cell transfusions. CONCLUSIONS: Splenic irradiation with a contemporary radiotherapeutic approach offers safe and effective palliation of symptomatic splenomegaly in myeloproliferative disorders.

Myelosuppression toxicity of palliative splenic irradiation in myelofibrosis and malignant lymphoma.

OBJECTIVES: Distinctive splenomegaly resulting from extramedullary hematopoiesis and infiltration of neoplastic cells is observed in some patients with myelofibrosis (MF) or malignant lymphoma. Palliative splenic irradiation is known to be effective for such patients and is widely performed. However, little is known about the biological mechanism of palliative splenic irradiation. Various reports have focused on irradiation doses, in terms of efficacy and safety. We examined the toxicity of myelosuppression and the timing of the platelet, white blood cell, and red blood cell count nadirs within 3 months after the start of irradiation in a total of eight patients with MF or malignant lymphoma, all of whom underwent palliative splenic irradiation at our hospital between 2004 and 2013. METHODS: Five patients with idiopathic MF and three patients with non-Hodgkin's lymphoma (NHL) treated with splenic irradiation between 2004 and 2013. Of the three patients with NHL, two had diffuse large B-cell lymphoma and one had mantle cell lymphoma. There were four male and four female patients, with median age of 61 years (range, 51-73). Patients with MF received irradiation at 20-100 cGy per fraction dose; four patients received irradiation five times a week and one patient received irradiation three times a week. In three of these patients, the irradiation dose was gradually increased while observing for hematotoxicity. Patients with NHL received irradiation at a fraction dose of 150-200 cGy, and all received irradiation five times a week. Irradiation was terminated when we judged symptoms to be alleviated, splenomegaly reduced, or efficacy to be poor. With regard to the total irradiation dose, 175, 320, 400, 600, and 640 cGy were given to one MF patient each, and 1050 and 3000 cGy were given to one and two NHL patients, respectively. RESULTS: Symptoms diminished or disappeared in five of the six symptomatic patients (83%). A reduction in the size of the spleen was confirmed in five of six patients (83%) with splenomegaly. For MF, the platelet count nadir was observed at week 3 in two patients, week 5 in two, and week 6 in one patient. For NHL, it was observed at week 1 in one patient, week 4 in one, and week 9 in one patient. For MF, the white blood cell count nadir was observed in at week 2 in one patient, week 3 in two, and week 5 in two patients. For NHL, it was observed at week 1 in one patient and week 4 in two patients. For MF, the red blood cell count nadir was observed at week 1 in two patients, week 3 in one, week 7 in one, and week 8 in one patient. For NHL patients, it was observed at week 1 in one patient, week 4 in one, and week 9 in one patient. Discussion There was a trend for the nadir to be steeper in patients with MF than in those with NHL. With regard to the total dose, symptoms diminished at the minimum dose of 175 cGy in MF patients, whereas the maximum dose of 3000 cGy was not effective in NHL patients. These observations suggest that a splenic lesion in NHL patients may be the primary site of neoplastic cell infiltration and that extramedullary hematopoiesis may not necessarily occur in the spleen. CONCLUSION: Although palliative irradiation of splenic lesions in patients with MF or NHL is safe and effective, optimal irradiation doses may differ for MF and NHL. More cases need to be accumulated to elucidate these differences.

Low-dose splenic irradiation in symptomatic congestive splenomegaly: report of five cases with literature data.

BACKGROUND: To show effectiveness of low-dose splenic irradiation in symptomatic congestive splenomegaly. METHODS: Five patients were referred to our department for symptomatic congestive splenomegaly within three years. Primary diseases were autoimmune hepatitis with liver cirrhosis (n=2), cystic fibrosis (n=1), granulomatous liver disease (n=1) and Werlhof disease with liver cirrhosis (n=1). Mean age was 54 years (range: 36-67). Patients received splenic irradiation with a total dose of 3 Gy (single dose: 0.5 Gy). One patient was re-irradiated after long-term failure with the same treatment schedule. RESULTS: In four patients long term relief of splenic pain could be observed during the follow-up time of median 20 (range: 2-36) months. Four patients showed haematological response after irradiation with an increase of erythrocytes, leucocytes and/or platelets. A slightly decrease in spleen size was found in two patients. CONCLUSIONS: Low-dose splenic irradiation in symptomatic congestive splenomegaly is feasible and perhaps as effective as in lympho-and myeloproliferative malignancies regarding pain relief and haematological response.

General theory of predictive dosimetry for yttrium-90 radioembolization to sites other than the liver.

Modern advances in interventional radiology and nuclear medicine may now allow for safe and effective 90Y radioembolization to sites other than the liver. A general theory of predictive dosimetry based on the MIRD schema is proposed, adapted from the original partition model for liver 90Y radioembolization.

Radioembolization of the spleen: a revisited approach for the treatment of malignant lymphomatous splenomegaly.

Intraarterial administration of (90)Y microspheres to the spleen in patients with malignant lymphoma was mentioned once in the literature in 1973. This case study illustrates the potential indication of selective internal radiotherapy in a heavily pretreated patient with highly refractory disease with a marginal zone lymphoma in leukemic phase and symptomatic splenomegaly. We describe the clinical course of disease; the biological and clinical response to the treatment after radioembolization; and simulation and dosimetry by multimodal imaging via single-photon emission computed tomography and computed tomography. The advantages of radioembolization for the management of lymphomatous splenomegaly are discussed.

Low dose palliative radiotherapy for splenomegaly in hematologic disorders.

Splenomegaly (SM) is a common complication in hematologic disorders often associated with hypersplenism, and may cause pain, epigastric discomfort and variable systemic effects due to cytopenias. We retrospectively evaluated the results of palliative splenic irradiation (PSI) in terms of symptomatic relief in patients with hematologic disorders. In 1998-2006, 32 patients with hematologic disorders (median age 57) received 52 courses of PSI for SM. Twenty-one patients (66%) were diagnosed with myeloproliferative disorders (MPD), five patients (16%) had malignant lymphoma (ML), five patients (16%) had chronic lymphocytic leukemia (CLL) and one patient (3%) had hairy cell leukemia. Splenomegaly was accompanied by pain, anemia, thrombocytopenia and cachexia. Radiation therapy to the entire spleen was delivered by two parallel opposed fields using 0.5 Gy daily fractions given 5 days per week to a total dose of 6-10 Gy. PSI resulted in splenic size reduction in 78.8%, improvement of anemia in 75% and improvement of thrombocytopenia in 63.5% of PSI courses. The median survival (MS) of patients with MPD, CLL and ML was 45, 10 and 5 months, respectively. The MS of responders to PSI versus non-responders was 45 and 16 months, respectively (hazard ratio 0.17; p = 0.03; 95% confidence interval 0.035-0.84). In our hands, low dose PSI provided effective palliation for patients with hematologic disorders with SM. Splenic re-irradiation was feasible without excessive toxicity.

Splenic irradiation in hematologic malignancies and other hematologic disorders--single institution experience.

Splenic irradiation has long been known as a palliative treatment modality in patients with various malignant hematologic diseases aiming to ameliorate clinical symptoms of splenomegaly as well as clinical sequels of hypersplenism. It provides considerable effect with low toxicity although exact radiotherapy dose and fractionation schedule are not known. During the 1996-2010 period, eleven patients were treated at our institution with splenic irradiation. They received 16 courses of fractionated radiotherapy. There were six patients with non-Hodgkin's lymphoma, four with chronic lymphocytic leukemia, and one patient with myelofibrosis. The median of the dose received was 7 Gy, while the median of dose received per fraction was 1 Gy. Both parallel opposed anterior-posterior fields and tangential fields were used. Due to the clinical target volume shrinkage, the treatment field was reduced in 44% of courses. Of the courses initiated for symptom control, 71% resulted in effective palliation, whereas of the courses started to treat hematologic sequels of hypersplenism 50% produced desirable effects. The most common side effects included thrombocytopenia and anemia. Splenic irradiation provides effective and low-toxic palliation of symptoms but it is much less successful in treating hematologic disorders caused by hypersplenism.

Radiotherapy of splenomegaly : a palliative treatment option for a benign phenomenon in malignant diseases.

PURPOSE: Since the 20(th) century, radiotherapy (RT) has been used for treatment of symptomatic splenomegaly (SM). SM occurs in association with hematologic disorders. The purpose of this analysis was to determine the indication, treatment concepts, and efficiency of RT. MATERIAL AND METHODS: Clinical features, treatment concepts, and outcome data during the past 20 years were analyzed. Endpoints were pain relief, symptomatic and hematological response, and treatment-related side effects. RESULTS: From 1989-2009, a total of 122 patients received 246 RT courses because of symptomatic SM. Overall 31 patients had chronic myelogenous leukemia (CML), 37 had chronic lymphocytic leukemia (CLL), 23 had osteomyelofibrosis (OMF), 17 had polycythemia vera (PV), 5 had acute myelogenous leukemia, 4 had idiopathic thrombocytopenic purpura (ITP), 3 had non-Hodgkin lymphoma (NHL), and 2 had multiple myeloma (MM). Patients were treated with (60)Co gamma rays or 5-15MV photons. The fraction size ranged from 10-200 cGy and the total dose per treatment course from 30-1600 cGy. Significant pain relief was achieved for 74.8% of the RT courses given for splenic pain. At least 50% regression was attained for 77% of the RT courses given for SM. 36 patients died within 2 months due to the terminal nature of their disease. Of the RT courses applied for cytopenia, 73.6% achieved a significant improvement of hematological parameters and reduction of transfusion need. Notable hematologic toxicities were reported < EORTC/RTOG II°. CONCLUSION: The present analysis documents the efficacy of RT. In addition, RT as a palliative treatment option for symptomatic SM should not be forgotten.

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.

Treatment of splenic marginal zone lymphoma: splenectomy versus rituximab.

Splenic marginal zone lymphoma (SMZL) is an uncommon indolent B-cell lymphoma causing marked splenic enlargement with CD20-rich lymphoma cells infiltrating blood and bone marrow. In the pre-rituximab era, the treatment of choice for patients with symptomatic splenomegaly or threatening cytopenia was splenectomy, since chemotherapy had limited efficacy. Responses to splenectomy occurred in approximately 90% of patients. However, SMZL patients are often elderly and poor surgical risks. Since approval of rituximab, treatment of such patients with the anti-CD20 antibody both alone or in combination with chemotherapy has shown remarkable responses. In retrospective series of rituximab monotherapy totaling 52 patients, including both chemotherapy-naive and -refractory patients, overall responses of 88% to 100% were noted with marked and prompt regression of splenomegaly and improvement of cytopenias. Sustained responses occurred both with and without rituximab maintenance in 60% to 88% of patients at 3 years. Relapsed patients responded to second courses of rituximab monotherapy. Overall survival was comparable to that reported following splenectomy. Rituximab in combination with purine nucleosides may provide further improvement in progression-free survival; however, confirmatory prospective trials are necessary. These results suggest that splenectomy should no longer be considered as initial therapy for SMZL but rather as palliative therapy for patients not responsive to immunotherapy with or without chemotherapy.