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 before allogeneic stem cell transplantation for myelofibrosis.

Splenectomy before allogeneic stem cell transplantation (ASCT) for patients with myelofibrosis (MF) remains a matter of debate, and conflicting results have been reported to date. The procedure seems to fasten post-transplant hematological recovery, but it does not have an impact on survival. The role of pre-transplant splenic irradiation (SI) is much more difficult to evaluate. Forty-four patients (25 males and 19 females) with MF at median age of 49 years at diagnosis (range 14-67) underwent ASCT. The post-transplant outcome was compared between irradiated and non-irradiated patients. Eleven patients received irradiation before transplantation. Median dose of radiation was 1000 cGy (range 600-2400). There was no difference in median time to engraftment between patients with and without previous radiotherapy. Acute and chronic graft versus host disease (GVHD) occurred in 47% and 36% of patients, respectively. There was no difference in GVHD incidence between groups. Eight patients relapsed/progressed in irradiated group versus 17 in non-irradiated (70% vs. 51%; p = 0.3). Transformation to acute myeloid leukemia was observed in 3 patients: 2 in irradiated and 1 in non-irradiated group. In total, 22 patients died with no statistical difference in death rate between irradiated and non-irradiated subjects. The probability of overall survival after transplant for the entire cohort at 2 years was 54% (72% for irradiated and 48% for non-irradiated patients; p = 0.25). Splenic irradiation prior to ASCT for myelofibrosis has not beneficial effect on post-transplant outcome.

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.

Allogeneic hematopoietic cell transplantation for myelofibrosis using fludarabine-, intravenous busulfan- and low-dose TBI-based conditioning.

Graft failure is one of the major barriers to the success of allogeneic hematopoietic cell transplantation (HCT) in myelofibrosis (MF). We report our institutional experience with 27 MF patients who underwent HCT using fludarabine-, intravenous BU- and low-dose total body irradiation (FBT)-based reduced-intensity (n=20) or full-intensity (n=7) conditioning regimens. Eight patients had prior exposure to JAK1/2 inhibitor therapy; six patients received JAK1/2 inhibitors leading on to HCT and two patients received transplant at the failure of JAK1/2 inhibitor therapy. No adverse impact of JAK1/2 inhibitor therapy was observed on early post-transplant outcomes. All evaluable patients had neutrophil recovery, and no primary graft failure was observed. Cumulative incidence of grades II-IV acute GVHD at day 100 was 48% (95% confidence interval (CI), 29-67%) and chronic GVHD at 2 years was 66% (95% CI, 49-84%). Cumulative incidences of nonrelapse mortality (NRM), relapse and probability of OS at 2 years were: 43% (95% CI, 12-74%), 10% (95% CI, 0-39%) and 56% (95% CI, 28-77%), respectively. FBT-based conditioning regimen has a favorable impact on engraftment; however, further efforts are required to reduce NRM.

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.

Repeated and preemptive palliative radiotherapy of symptomatic hepatomegaly in a patient with advanced myelofibrosis.

BACKGROUND: Patients with advanced myelofibrosis often suffer from symptomatic extramedullary hematopoiesis in spleen and/or liver. In case of drug-refractory disease splenomegaly is treated surgically, whereas hepatomegaly is palliated by radiotherapy (RT). CASE REPORT: A 56-year-old man with advanced and drug-refractory myelofibrosis suffered from extensive hepatomegaly with severe upper abdominal pain, satiety, weight loss, and fatigue 1.5 years after splenectomy. The patient was treated periodically with fractionated RT to the liver in order to obtain symptom control and to prevent severe symptom recurrence. RESULTS: After 2 Gy fractionated RT to a treatment field encompassing nearly the whole liver, symptoms improved and liver size decreased without severe side effects. This treatment regimen was successfully conducted 3 times in trimonthly intervals. Because symptoms recurred periodically, we then continued RT on a preemptive basis in monthly intervals and with single-dose irradiation. The patient responded well to 1 Gy preemptive single-dose RT to the liver, but not to 0.5 Gy single-dose partial liver irradiation. CONCLUSION: RT is effective in palliation of hepatomegaly in advanced myelofibrosis. Even preemptive RT can benefit selected patients with advanced disease and periodical recurrence of symptoms.

New and old treatment modalities in primary myelofibrosis.

The treatment of primary myelofibrosis (PMF) remains essentially palliative. Conventional modalities include a wait-and-see approach for asymptomatic patients, oral cytolytic drugs such as hydroxyurea for the hyperproliferative forms of the disease, androgens or erythropoietin for the anemia, and splenectomy in selected patients. These therapeutic modalities improve the patients' quality of life but have no impact on survival. Newer therapies for PMF are currently being used. Antiangiogenic and immunomodulatory drugs such as thalidomide and lenalidomide are associated with frequent side effects but have shown certain efficacy, especially for the anemia and thrombocytopenia. The association of low-dose thalidomide with prednisone has better tolerability, and it is also effective. Tyrosine kinase inhibitors such as imatinib have also been used, but their efficacy is limited. Tipifarnib, a farnesyltransferase inhibitor, has shown certain effects in the anemia. Allogeneic stem cell transplantation (SCT) is the only curative therapy for PMF. Its standard modality has an associated mortality of 30%, and it is indicated in younger patients with high-risk disease or disease resistant to conventional treatment. Reduced-intensity conditioning allogeneic SCT is associated with low mortality while maintaining a curative potential, and until longer follow-up is available, it can be used in patients aged 45-70 years old with high- or intermediate-risk myelofibrosis or myelofibrosis resistant to treatment. Autologous SCT is a palliative measure that can be considered in patients with resistant disease, who lack a suitable donor. Newer immunomodulatory drugs, proteasome inhibitors, hypomethylating agents, and JAK2 inhibitors are currently being tested.

Different outcome of allogeneic transplantation in myelofibrosis using conventional or reduced-intensity conditioning regimens.

Allogeneic haematopoietic stem cell transplantation remains the only curative treatment of myelofibrosis with myeloid metaplasia (MMM). Previous reports have indicated significant treatment-related mortality (TRM) for patients transplanted after myeloablative conditioning but superior survival has been reported after reduced-intensity conditioning (RIC). We report the results of a survey of all allogeneic transplantations for MMM performed in Sweden at six transplant units between 1982 and 2004. Twenty-seven patients were transplanted; 17 with a myeloablative conditioning regimen and 10 with RIC. The median age was 50 years (5-63 years) at transplantation. After a median follow up of 55 months, 20 patients are alive. TRM was 10% in the RIC group and 30% in the myeloablative group. There was no difference in survival for high or low-risk patients according to Cervantes score or between sibling and unrelated donor transplantations.

Surgical and radiotherapeutic approaches for myelofibrosis with myeloid metaplasia.

Sequestration of circulating immature myeloid progenitors in the chronic myeloproliferative disorder myelofibrosis with myeloid metaplasia (MMM) leads to extramedullary hematopoiesis (EMH), as well as end organ enlargement and dysfunction. When medical therapy is inadequate to control symptomatic myeloproliferation, both surgical resection and/or external beam radiotherapy may provide palliative cytoreduction in specific situations. Therapeutic splenectomy may provide relief of pain, mass effect, an improvement in cytopenias, or even palliation of portal hypertension. However, the risks of perioperative and long-term complications limit the use of splenectomy in MMM to specific candidates. In addition to splenectomy, portal hypertension has been palliated by either elective esophageal variceal ligation or porto-systemic shunting (through either open or invasive radiographic means). External beam radiotherapy can provide palliative cytoreduction in afflicted organs, with the greatest benefit seen in the lungs and spine. Splenic radiation also can provide a decrease in the size of the organ but carries the risk of myelosuppression and potentially increases the risk associated with subsequent splenectomy. Hepatic and abdominal radiation may palliate hepatomegaly and/or ascites, but cytopenias are common and responses brief. Novel therapies aimed at the pathogenesis of the disorder are needed for more efficacious and targeted therapy of MMM.

Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment.

OBJECTIVE: To define associated clinical conditions, pathology, natural history, and treatment outcome of nonhepatosplenic extramedullary hematopoiesis (NHS-EMH). PATIENTS AND METHODS: We retrospectively reviewed the medical charts of all patients identified as having NHS-EMH from 1975 to 2002. Diagnosis was made by tissue biopsy, fine-needle aspiration biopsy, or radionuclide bone marrow scanning. RESULTS: We identified 27 patients with antemortem diagnosis of NHS-EMH. The most common associated condition and disease site were myelofibrosis with myeloid metaplasia (MMM) (in 18 patients [67%]) and the vertebral column (in 7 patients [26%]; all involving the thoracic region), respectively. At the time of diagnosis of NHS-EMH, concurrent splenic EMH (in 22 patients [82%]; 15 [56%] had undergone splenectomy) and red blood cell transfusion dependency (in 12 patients [44%]) were prevalent. Of the 27 patients, 9 (33%) required no specific therapy. Specific therapy was radiation (in 7 patients with a 71% response rate) and surgical excision (in 6 patients with a 67% response). Treatment-associated complications were limited to surgery. Radiation therapy was not used in the non-MMM group, but low-dose radiation therapy was used in the MMM group for paraspinal or intraspinal EMH (median dose, 1 Gy; range, 1-10 Gy), pleural or pulmonary disease (median dose, 1.25 Gy; range, 1.00-1.50 Gy), and abdominal or pelvic disease (median dose, 2.02 Gy; range, 150-4.50 Gy). Median survival after the diagnosis of NHS-EMH was 13 months in the MMM group and 21 months in the non-MMM group. CONCLUSIONS: This retrospective study suggests that NHS-EMH is rare, is often associated with MMM, and preferentially affects the thoracic spinal region. Asymptomatic disease may require no specific treatment, whereas symptomatic disease is best managed with low-dose radiation therapy.