Treatment options for hydroxyurea-refractory disease complications in myeloproliferative neoplasms: JAK2 inhibitors, radiotherapy, splenectomy and transjugular intrahepatic portosystemic shunt.

Clinical care of patients with polycythemia vera, essential thrombocythemia and myelofibrosis (MF) requires not only a broad understanding of general treatment principles but also familiarity with the management of hydroxyurea-refractory disease complications. The latter include progressive splenomegaly, symptomatic portal hypertension (e.g. ascites, variceal bleeding), pulmonary hypertension, bone pain, intractable pruritus, constitutional symptoms (e.g. fatigue, night sweats) and cachexia (i.e. loss of lean body mass, general ill health, poor appetite). Some of these symptoms are directly or indirectly related to extramedullary hematopoiesis (EMH) and others to proinflammatory cytokine excess. Results from recent clinical trials of JAK inhibitors suggest remarkable activity in MF-associated constitutional symptoms, cachexia, pruritus and hydroxyurea-refractory splenomegaly. Involved-field radiotherapy is best utilized in the setting of EMH-associated symptoms, including ascites, bone (extremity) pain and pulmonary hypertension. Splenectomy is indicated in the presence of drug-refractory splenomegaly and frequent red cell transfusion requirement. Transjugular intrahepatic portosystemic shunt is used to alleviate symptoms of portal hypertension.

Synchronous myeloproliferative and inflammatory disease of the nasal cavity and paranasal sinuses: an interesting differential diagnostic problem.

The authors present a case of synchronous manifestation of a myeloproliferative--extramedullary plasmocytoma--and a chronic inflammatory disease of the nose and the paranasal sinuses. They emphasise the importance of imaging techniques and immunohistochemistry in the differential diagnosis. They discuss on the basis of published articles the new classification, clinical manifestations, diagnostic and therapeutical approaches of this tumour belonging to the group of monoclonal gammopathies, which originates from an abnormal proliferation of mature B-lymphocytes, and is a rarity in the literature even nowadays.

EANM procedure guideline for 32P phosphate treatment of myeloproliferative diseases.

INTRODUCTION: (32)P phosphate was the first therapeutic radioisotope, used in leukaemia about 70 years ago. Since then, many new agents for haematological proliferations have been introduced successfully. Today there remains a distinct subgroup of elderly patients with polycythaemia vera and essential thrombocythaemia for whom (32)P is the most optimal treatment option, an assertion supported by two large studies with long follow-up. PURPOSE: The purpose of this guideline is to assist the nuclear medicine physician in treating and managing patients who may be candidates for (32)P phosphate therapy.

[Two patients with joint pain as initial presentation of a haematological malignancy]. / Twee patiënten met gewrichtsklachten als initiële presentatie van een hematologische maligniteit.

A 75-year-old man and a 53-year-old woman had longstanding joint pain, for which they had been treated with NSAIDs. When the symptoms worsened, a thorough diagnostic investigation was conducted that revealed myeloproliferative bone-marrow disorders in both patients. The man, who had polyarticular gout secondary to chronic myelomonocytic leukaemia, was able to maintain control of his joint pain with medical treatment. In the woman, with a history of stable joint pain due to polyarthritis, deterioration of the symptoms and the development of pancytopaenia led to a diagnosis of acute lymphocytic leukaemia; she died after receiving multiple courses of chemotherapy. The possibility of an underlying malignancy should be considered in patients with atypical symptoms in the locomotor system, an unexpected course or anomalous secondary symptoms.

Clinical indications and biological mechanisms of splenic irradiation in chronic leukaemias and myeloproliferative disorders.

Splenic irradiation (SI) was the first efficient treatment for chronic leukaemia, but with the emergence of effective drugs its use has been more and more restricted to advanced cases presenting with splenomegaly. But in selected patients who are not responsive or not suitable to drug treatment, SI may offer still an effective, low toxic and cost-effective palliative modality. Eight studies of SI in chronic lymphatic leukaemia (CLL) including 198 patients, six reports about SI in prolymphocytic leukaemia (PLL), including 18 patients, one study and six case reports about SI in hairy cell leukaemia (HCL) and nine studies about SI in myeloproliferative disorders has been analyzed. In CLL, symptoms of splenomegaly have been improved in 50-87% of all patients with overall doses between 4 and 10 Gy in mostly 1-Gy fractions. PLL seems to be more resistant to SI with a median response rate of 66%. Casuistic reports described also efficacy of SI in HCL patients using similar radiation schedules. Symptomatic relief is also provided by SI in myeloproliferative disorders using lower overall doses between 1 and 9 Gy with small single fractions of 0.25 Gy (median). Acute toxicity was low in lymphoid disorders, but higher in myeloproliferative disorders with severe cytopenia in 10-30% of all cases, indicating the need for a cautious fractionation schedule. Interestingly, even complete systemic remissions after SI in all types of lymphoproliferative disorders have been described. Different mechanisms underlying SI such as direct cell kill, immune modulation via changes in lymphocyte subsets or cytokine induction or "radiotherapeutic" splenectomy with high doses are discussed.

Treatment of the myeloproliferative disorders with 32P.

The use of radioactive phosphorus (32P) to treat the myeloproliferative disorders (chronic leukemia, polycythemia vera and essential thrombocythemia) began in 1939 when John H. Lawrence treated the first patient on the basis of work done in the laboratory animals that found localization of the radioisotope in the spleen, liver, bone and in leukemic cells sufficient to indicate a therapeutic potential. After World War II when 32P became widely available, it was used extensively to treat the chronic leukemias and polycythemia vera. Its use in the treatment of essential thrombocythemia began later in 1950. Today it is not widely used in the treatment of the chronic leukemia, if at all, its use in polycythemia vera appears to have decreased substantially and replaced by hydroxyurea, and its use in the management of essential thrombocythemia is not widespread. In each instance it has been replaced by a drug developed for use in cancer chemotherapy, and in some instances by interferon. It probably has wider use in polycythemia vera in the rest of Western Europe than in the UK, and there are cogent reasons to suggest that it may be the best tool for the treatment of polycythemia vera. Thus have we discarded a treatment modality that in polycythemia vera may be the best?

[Radiotherapy in leukemia excluding total body irradiation]. / Irradiations pour leucémie à l'exclusion de l'irradiation corporelle totale.

Radiation techniques and indications in leukemias have been described in detail, yet prophylactic cranial irradiation in acute leukemia still has few indications. Cerebrospinal and testicular irradiation are reserved for relapsing disease. Radiation usually results in rapid functional improvement when used in neurologic emergencies and symptomatic neurologic or gross tumors relapses. Nevertheless, the improvements recently obtained by systemic chemotherapy have resulted in the reduction in the use of irradiation, especially in children, where it was considered deleterious with neuropsychological sequellae. Splenic irradiation remains useful for symptomatic myeloproliferative syndrome.

Splenic irradiation in the palliation of patients with lymphoproliferative and myeloproliferative disorders.

INTRODUCTION: Splenic irradiation is an accepted mode of treatment for palliation of hypersplenism and splenic pain for patients with lymphoproliferative or myeloproliferative disorders. However, results are conflicting regarding the duration of palliation and the toxicity associated with this treatment. METHODS: Twenty-five patients with lymphoproliferative or myeloproliferative disorders were treated with splenic irradiation for palliation of splenomegaly and pain. The spleen was measured and pain and toxicity were assessed during radiation therapy. RESULTS: Splenomegaly and splenic pain decreased in 60 percent and 91 percent of patients, respectively. Radiation doses higher than 500 cGy appeared to be more effective than lower doses in reducing the spleen size in patients with chronic lymphocytic leukemia. Regression of splenomegaly and pain relief were maintained for less than one year and more than six months, respectively. Acute radiation toxicity resulted in the cessation of radiotherapy in two patients. CONCLUSION: Splenic irradiation is effective in the short-term palliation of splenomegaly and pain and may be most useful in the subset of patients with a life expectancy of less than one year. Terminally ill patients with splenomegaly secondary to lymphoproliferative or myeloproliferative disorders may benefit from splenic irradiation to minimize pain and pressure symptoms in addition to possible reduction of narcotic use.

Refractory ascites in the chronic myeloproliferative syndrome: a case report.

In a patient with myelofibrosis, tense ascites refractory to conventional therapy resulted from extensive seeding of the peritoneum with colonies of extramedullary haematopoiesis. Whole abdominal radiation was found to be effective and well tolerated, and brought about prompt and lasting resorption of the exudate, with weight reduction and improvement in performance status from 50% to 90% on the Karnofsky rating.

Bone marrow transplantation for myelodysplastic and myeloproliferative syndromes.

Twenty patients (age range, 4 to 48 years; median age, 36 years) with de novo or drug-induced myelodysplastic syndromes or myeloproliferative disorders were treated with myeloablative immunosuppressive therapy followed by bone marrow transplantation (BMT). Four preparative regimens were used; three regimens consisted of combined total body irradiation (TBI) and chemotherapy and one of combination chemotherapy only. One patient received marrow from his identical twin brother, whereas the other 19 patients were grafted with marrow from histocompatible siblings. In 19 patients the abnormal clone was at least temporarily ablated, while in one patient the congenital myelodysplasia persisted. Eight patients are alive and well for +108 to +3,359 days post-transplantation. Nine patients died of transplant-related complications (six of interstitial pneumonia, two of gastrointestinal bleeding, and one of fungal sepsis) and three patients died with persisting or recurring disease. One patient with a late recurrence has undergone a second successful bone marrow transplant procedure. Outcome of BMT was not related to French-American-British (FAB) type, marrow fibrosis, cytogenetic abnormalities, or preparation regimen. Marrow transplantation as a means of providing long-term disease-free survival and possible cure should be considered in patients if a suitable donor is available.

Hyperfractionated total body irradiation as part of autologous bone marrow transplantation.

On 14 patients with acute leukemia and non-Hodgkin lymphoma autologous bone marrow transplantation (ABMT) was performed together with high dose cyclophosphamide and hyperfractionated total body irradiation. The radiotherapy was given at a total dose of 13.2 Gy distributed over eleven fractions of 1.2 Gy and four days. All eleven patients transplanted in complete remission are alive, among them ten in unmaintained complete remission at a longest observation time of two years.

[How extensive are the present indications for bone marrow transplantation?]. / Wie breit ist heute der Indikationsbereich der allogenen Knochenmarktransplantation?

Bone marrow transplantation (BMT) is emerging as a valuable therapeutic approach to a number of diseases that are usually or uniformly fatal. In a general review, recent experience with BMT in acute leukemia, chronic granulocytic leukemia and severe aplastic anemia is summarized.

The effect of daily low dose gamma irradiation on growth and differentiation of human myeloid leukaemic bone marrow in diffusion chambers.

Bone marrow from each of 8 untreated patients with myeloproliferative disorders was grown in diffusion chambers in 760 rad total body irradiated rats. Rats were then exposed to 11.5, 57.5, or 108.5 rad daily for 14-2l d and cell growth compared to that detected in unirradiated chambers. Cells from acute myelogenous leukaemia patients exposed to 11.5 rad per d grew for 11-21 d and there was no consistent stimulation of differentiation of immature granulocytic cells to mature granulocytes that was attributable to irradiation. Cells from a chronic myeloid leukaemia patient in chronic phase or blast crisis, and a polycythaemia vera patient with myeloid metaplasia showed significant morphologic differentiation from immature to mature granulocytes in control chambers with no additional effect of daily irradiation. Marrow specimens from 2 AML patients exposed to each of 3 daily dose fractions over 14 d revealed a dose-dependent decrease in immature granulocytes with no persistent increase in mature granulocytes. In both irradiated and control chambers, macrophages increased over 21 d. Thus, cells from patients with myeloproliferative disorders may not necessarily differentiate to mature granulocytes following in vivo exposure to ionizing irradiation.

Radionuclide therapy of hematologic disorders.

32P is effective therapy for polycythemia and primary thrombocytosis. The Polycythemia Vera Study Group is comparing radioactive phosphorus with alkylating agents to determine relative efficacy. Less well investigated is the effectiveness of 32P vs. busulfan in chronic granulocytic leukemia. Endolymphatic administration of radiopharmaceuticals may play a role in the therapy of infradiaphragmatic lymphoma. Among the radionuclides that have at times been used in hematology are 32P, 198Au 24Na, 76As, 89Sr, 52Mb, 54Mn, 91Y, 95Zr, 95Cb, 111Ag, 109Pd, 131I, 185W, and 192Ir. As stated, 32P has proven single most efficacious agent. The hematologic diseases that have been treated include both malignant and benign conditions. Among the malignant conditions are polycythemia vera, agnogenic myeloid metaplasia, thrombocythemia, leukemia, Hodgkin's disease, and multiple myeloma. Hemophilia, and Osler--Weber--Rendu disease are among the benign entities in which the agents have been tried. Polycythemia and thrombocythemia remain those in which the greatest success has been achieved.

[Irradiation of the spleen during malign diseases of the blood (author's transl)]. / Zur Milzbestrahlung bei malignen hämatologischen Krankheiten

The results of splenic irradiation in 8 patients with neoplastic hematologic diseases are compared with those previously published. Although only 2 of our 8 cases showed a remission, 7 of the 8 patients showed a decrease in spleen size and a subjective improvement. The regularly observed and often severe pancytopenia after splenic irradiation was in no apparent relation to the dose applied. The indications and the dosage of radiotherapy of the spleen are discussed.