1205 Long Term Treatment of Myeloproliferative Disease with Interferon-a-2b Feasibility and Efficacy Harriet S. Gilbert, M.D. Albert Einstein College of Medicine, Bronx, New York. BACKGROUND. Recombinant interferon-a-2b (rIFN-a-2b) has shown therapeutic potential in patients with chronic myelogenous leukemia and other myeloproliferative disorders (MPDs), including the ability to suppress the abnormal hematopoietic clone and to reverse myelofibrosis. This study was conducted to evaluate further the efficacy and safety of rIFN-a-2b in a large group of patients with polycythemia vera, essential thrombocythemia, or agnogenic myeloid metaplasia and to determine maintenance of response after treatment discontinuation. METHODS. Induction therapy began with subcutaneous rIFN-a-2b at 5.0 3 106 IU/day until a complete or partial response was achieved. Treatment continued at 2.5 3 106 IU/day until spleen size and hematologic parameters stabilized. RESULTS. Fifty-four patients were studied (median follow-up, 7.3 years); at last follow-up 27 patients still were participating (median follow-up, 3.8 years). Twenty-four of 24 patients with thrombocythemia (100%) and 14 of 14 patients with hyperleukocytosis (100%) responded to induction therapy, whereas 26 of 39 patients (67%) experienced . 10% decrease in splenomegaly. Thirty-nine of 54 patients (72%) maintained response for a median of 39 weeks after withdrawal of rIFN-a-2b; repeat courses in previously responding patients produced similar results. The survival rate at 8 years was 60%. rIFN-a-2b generally was well tolerated, but toxicity caused treatment withdrawal in 7 patients (13%). CONCLUSIONS. rIFN-a-2b can produce regression of splenomegaly and control of leukocyte and platelet counts in patients with MPD. These responses are sustained for prolonged periods in some patients after therapy discontinuation. In patients with recurrent disease, disease control can be attained again with reinitiation of rIFN-a-2b. Therefore this therapy should be an important treatment consideration for patients with MPD. Cancer 1998;83:1205–13. © 1998 American Cancer Society. KEYWORDS: interferon, myeloproliferative disease, long term efficacy, therapy. Preliminary results presented at the Annual Meeting of The American Society of Hematology, Seattle, Washington, December 1–5, 1995. Supported by a research grant from Schering Corporation, Kenilworth, New Jersey. Address for reprints: Harriet S. Gilbert, M.D., Albert Einstein College of Medicine, 115 E. 72nd Street, New York, NY 10021. Received August 22, 1997; revision received March 2, 1998; accepted March 23, 1998. © 1998 American Cancer Society C hronic myeloproliferative disorders (MPDs) result from monoclonal expansion of abnormal pluripotent stem cells and are characterized by abnormalities in hematopoietic cellular proliferation, quantitative and qualitative alterations in bone marrow and peripheral blood cells, and fibrosis and extramedullary expansion of the blood-forming organ.1–10 The latter sequela is manifested by hepatosplenomegaly, which may be debilitating even before cytopenias, varices, gastrointestinal bleeding, or ascites occur. The chronic progressive myelofibrosis and extramedullary expansion may be mediated largely by a premalignant megakaryocyte population derived from the neoplastic clone. Hematopoietic stem cells exhibit nonrandom chromosomal abnormalities in 33% of patients with MPD.4 – 6 1206 CANCER September 15, 1998 / Volume 83 / Number 6 Conventional treatment for MPD has been comprised either of mechanical removal of increased hematopoietic populations by phlebotomy, apheresis, and splenectomy or of myelosuppression by external beam radiation, radioactive phosphorus, alkylating agents, and/or hydroxyurea.1–3 However, these approaches are only palliative, and the disease progresses inexorably, with debilitating abdominal organomegaly, transfusion dependency, bleeding, infection, and transformation into acute leukemia. Bone marrow transplantation has a curative but limited potential11-13 and may not be a suitable treatment option for many patients with MPD because of their age or debility, or because of the absence of appropriate donors. Furthermore, there is concern regarding complications relating to the procedure, particularly the risk of transmission of infectious disease.14 Given the inexorable course of MPD and the lack of effective treatments, a need exists for well tolerated therapies that can be initiated relatively early, before debilitating visceral organomegaly or end-organ damage occur. Recombinant human interferon-a(rIFN-a), a glycoprotein produced by genetic engineering, has shown significant activity in a variety of hematologic and nonhematologic conditions, including hairy cell leukemia,15,16 chronic myelogenous leukemia,17,18 high risk melanoma, and other variants of MPD.19 –25 In the latter patients, rIFN-a gradually decreased peripheral blood counts without unpredictable cytopenias, reduced visceral organomegaly, and produced durable, unmaintained remissions without hematologic rebound on the cessation of therapy. Recombinant IFN-a also has shown activity in reversing myelofibrosis and suppressing the abnormal hematopoietic clone. These clinical results support the findings of in vitro studies in which several classes of IFNs reportedly suppressed cultured human fibroblast growth and procollagen synthesis,26 –28 as well as cultured megakaryocyte proliferation and platelet production.29 Considering its reported therapeutic potential in MPD and its favorable safety profile,30 –32 rIFN-a-2b was studied to evaluate further its long term efficacy in patients with MPD and to determine the effect of treatment discontinuation on remission maintenance. METHODS Patients Males and females ages 18 – 85 years with a diagnosis of either polycythemia rubra vera, essential thrombocythemia, or agnogenic myeloid metaplasia, established through review of the case and relevant pathology specimens, were eligible for study enrollment. Any previous treatment for MPD must have been com- pleted at least 2 weeks before initiation of rIFN-a-2b, or 2 months before in the case of radioactive phosphorus. The study was approved by the Institutional Review Board, and informed written consent for study participation was obtained from all patients. Exclusion criteria included evidence for evolution into a blastic phase; a Karnofsky performance status , 60%; New York Heart Association status $ 3; pregnancy or lactation; severe intercurrent infection or surgery within the previous 2 weeks (unless fully recovered); serum creatinine . 2 mg/dL; serum aspartate aminotransferase, bilirubin, or prothrombin time . 23 the upper limit of normal; platelet count , 40 000 cells/mL; and inability to comply with the treatment program or provide informed consent. Use of effective contraception was required for all women of childbearing potential. Treatment rIFN-a-2b (INTRONt A; Schering Corporation, Kenilworth, NJ) was obtained commercially. Each dose was prepared by reconstituting the drug with the supplied diluent, and the total dose was administered subcutaneously (s.c.). An induction course comprised of 5.0 3 106 IU/ day of rIFN-a-2b was administered until patients achieved a complete or partial response. Therapy continued in the absence of Grade 3 or 4 toxicity (World Health Organization criteria), disease progression, infection with a leukocyte count , 1000 cells/mL, or hemorrhagic complication with a platelet count , 20,000 cells/mL. Maintenance treatment comprised of 2.5 3 106 IU/day s.c. of rIFN-a-2b then was administered until stabilization of spleen size and hematologic parameters was achieved. (Titration was based on myelosuppression or toxicity.) Thereafter, rIFN-a-2b was discontinued, and patients were observed for any signs of increased disease activity. Such an increase was an indication for readministration of rIFN-a-2b therapy. The daily dose of rIFN-a-2b was modified during both the induction and maintenance phases in the event of myelosuppression or other toxicity. The rIFNa-2b dose was withheld in the event of Grade 3 or 4 toxicity, disease progression, infection with a leukocyte count , 1000 cells/mL, or hemorrhagic complication with a platelet count , 20,000 cells/mL. Concomitant therapy allowed during the study included phlebotomy to maintain a hematocrit # 45%, allopurinol, acetaminophen, antihistaminics, antiplatelet aggregating therapy, nonmyelosuppressive medications needed to treat coexisting disease, red blood cell or platelet transfusions, and corticosteroids (prednisone or equivalent, not to exceed 10 mg/day). rIFN-a-2b in Myeloproliferative Disease/Gilbert Response Evaluation and Criteria Prior to the initiation of rIFN-a-2b therapy, all patients were evaluated with medical history and physical examination. The laboratory tests performed included hematology (complete blood count with differential, platelets, and reticulocytes), bone marrow aspirate and biopsy, prothrombin time/partial thromboplastin time, routine biochemistry, urinalysis, electrocardiogram, chest X-ray analysis, and technetium sulfur colloid scans of the bone marrow and liver/spleen. Total spleen size was measured by palpation as the sum of the vertical and horizontal span using the left costal margin and left midclavicular line as reference points. Patients were evaluated weekly during the first 4 weeks of induction therapy and then every other week if they had no Grade 3 or 4 toxicities. A complete blood count with differential and platelets were determined at each visit, and routine serum biochemistry and urinalysis were performed monthly. Patients were evaluated for response to rIFN-a-2b therapy after 40 and 52 weeks of treatment. All baseline studies were repeated at the 40-week visit; hematology, bone marrow aspirate and biopsy, serum biochemistry, and urinalysis were repeated after 52 weeks. A complete response was defined as normalization of the complete blood count (i.e., leukocyte count . 4000 cells/mL; absolute granulocytes . 1500 cells/mL; hemoglobin, 12–18 g/dL and/or hematocrit, 35–52%; platelet count 125,000 –500,000 cells/mL); resolution of transfusion dependency; absence of hemorrhagic and/or thrombotic events during the preceding 3 months; nonpalpable spleen; and normalization of bone marrow histology (cellularity, 30 –50%; myeloid:erythroid precursor ratio, 2:1 to 5:1; normal morphology and maturation of all cell lines; decrease in bone marrow fibrosis). Patients who met any one of the following criteria were judged to have a partial response: hemoglobin . 9 mg/dL without transfusion support and persisting for 4 weeks in patients entered because of anemia; platelet count, 70,000 – 800,000 cells/mL for at least 4 weeks and absence of significant hemorrhagic and/or thrombotic events for at least 3 months before assessment in patients enrolled because of thrombocytosis and/or a disorder of hemostasis; and $ 35% reduction in spleen size for patients enrolled because of symptomatic splenomegaly. Patients were divided into eight diagnostic groups—agnogenic myeloid metaplasia (AMM), postpolycythemia vera myeloid metaplasia (PPV-MM), postessential thrombocythemia myeloid metaplasia (PET-MM), active polycythemia vera with myeloid metaplasia (PV-MM), essential thrombocythemia (ET), polycythemia rubra vera (PV), atypical myelo- 1207 TABLE 1 Diagnostic Criteria Diagnosis Clinical criteria AMM Leukoerythroblastic peripheral smear (immature granulocytes, nucleated RBCs, dacryocytes) Increased reticulin and/or collagen on bone marrow biopsy Splenomegaly by physical or radiologic examination Absence of TB, lymphoma, or other disease associated with myelofibrosis Elevated RBC mass by 51Cr (males, .36 mL/kg; females, . 32 mL/kg) Normal arterial O2 saturation .90% Splenomegaly by physical or radiologic examination If splenomegaly absent, patient must have 2 of following: Leukocytosis . 12,000/mL in absence of fever or infection Thombocytosis . 400,000/mL Elevated leukocyte alkaline phosphatase . 100 Elevated B12 or B12 binding proteins Platelet count . 1 3 106/mL for 3 mo Hypercellular bone marrow with megakaryocyte hyperplasia Hemoglobin , 16 g/dL (males), , 14 g/dL (females) with normal RBC mass demonstrated by chromium study Absence of iron deficiency, chronic inflammatory disease, or second malignancy Absence of Philadelphia chromosome Myeloid metaplasia that evolved from PV Increased splenomegaly Increased bone marrow fibrosis Stabilization of diminution of RBC mass Leukoerythroblastosis featuring numerous teardrop poikilocytes Myeloid metaplasia that evolved from essential thrombocythemia Active PV with evidence of myeloid metaplasia Increased proliferation and/or dysplasia of more than one hematopoietic stem cell lineage; not classifiable under the typical myeloproliferative diseases Clinical and bone marrow findings indicative of acute megakaryocytic leukemia (i.e., acute myelofibrosis) that persists for .3 mo PV ET PPV-MM PET-MM PV-MM A-MPD SM AMM: agnogenic myeloid metaplasia; RBC: red blood cell; TB: tuberculosis; PV: polycythemia rubra vera; ET: essential thrombocythemia; PPV-MM: postpolycythemia vera myeloid metaplasia; PET-MM: postessential thrombocythemia myeloid metaplasia; A-MPD: atypical myeloproliferative disease; SM: subacute myelofibrosis. proliferative disorder (A-MPD), and subacute myelofibrosis (SM)— based on the diagnostic criteria established by the Polycythemia Vera Study Group.3,33 These criteria are described in Table 1. The median durations of the induction course of rIFN-a-2b, the second course of rIFN-a-2b therapy, and the periods of unmaintained response were calculated for each diagnostic group. The median time on the study protocol was calculated both for each diagnostic group and for the entire study population. Mean changes in leukocyte counts, platelet counts, hematocrit levels, and spleen size also were determined by diagnostic group. In addition, response to 1208 CANCER September 15, 1998 / Volume 83 / Number 6 TABLE 2 Baseline Profile of Study Population TABLE 3 Patient Outcomes Summary Variable No. Males Females Median age (yrs) (range) Diagnosis by Polycythemia Vera Study Group AMM PPV-MM PET-MM PV-MM ET PV A-MPD SM Time from diagnosis to start of rIFN-a-2b therapy (yrs) ,1 .1 (range, 2–33) Therapeutic indications for rIFN-a-2ba Symptomatic splenomegaly Thrombocythemia Hyperleukocytosis Portal hypertension Previous therapy No treatment Chemotherapy 33 21 Percentage 60% 40% 61 (22–77) 14 6 2 17 3 8 3 1 30% 11% 4% 31% 5% 15% 5% 2% 9 45 17% 83% 39 24 14 4 72% 44% 26% 7% 25 29 46% 54% Median time on study (yrs) (range) All patients (n 5 54) Active (i.e., ongoing) patients (n 5 27) Study termination (total) Adverse events Intercurrent illness Splenectomy Progressive hematologic disease Deaths (total) Lost to follow-up a 2.5 (0.12–8.1) 3.8 (0.8–7.8) 25 (46%) 7 (13%) 7 (13%) 5 (9%) 6 (11%) 22 (41%) (7.5 yearsa) 2 (4%) Median follow-up. rIFN-a-2b therapy was analyzed according to the indication for treatment (i.e., thrombocythemia, hyperleukocytosis, and splenomegaly). portal hypertension (4 patients). Some patients had more than one indication for treatment. Patient outcomes are summarized in Table 3. The median time on study for the entire group of 54 patients was 2.5 years (range, 0.12– 8.1 years). At last follow-up 27 patients still were participating in the study, with a median follow-up of 3.8 years (range, 0.8 –7.8 years). Twenty-five patients went off the study at the patient’s request or on the advice of the treating physician because of either adverse events (7 patients), intercurrent illness (7 patients), election to undergo splenectomy (5 patients), or progressive hematologic disease (6 patients). Sixteen of the patients removed from the study died (intercurrent illness: 6 patients; splenectomy: 4 patients; and progressive hematologic disease: 6 patients). The median time to death after the completion of rIFN-a-2b therapy was 0.92 years (range, 1 week-2.9 years). Two patients were lost to follow-up. RESULTS Hematologic and Spleen Outcomes Patients Table 4 summarizes the changes in spleen size and laboratory values that occurred after the induction course of rIFN-a-2b therapy, with patients categorized according to Polycythemia Vera Study Group diagnosis. Mean total spleen size was reduced by 17% in the AMM patients, 19% in the PPV-MM patients, 0.1% in the PET-MM patients, 33% in the PV-MM patients, and 73% in the PV patients. Increases in mean total spleen size of 56% and 7% occurred in the ET patients and A-MPD patients, respectively. Mean leukocyte counts were decreased by 0.2% in the AMM patients, 25% in the PPV-MM patients, 35% in the PET-MM patients, 59% in the PV-MM patients, 50% in the ET patients, 48% in the PV patients, and 22% in the A-MPD patients, and by 66% in the SM patient. Mean platelet counts were reduced in all but one of the diagnostic categories. The mean percent AMM: agnogenic myeloid metaplasia; PPV-MM: postpolycythemia vera myeloid metaplasia; PET-MM: postessential thrombcythemia myeloid metaplasia; PV-MM: active polycythemia vera with meyloid metaplasia; ET: essential thrombocythemia; PV: polycythemia rubra vera; A-MPD: atypical myeloproliferative disorder; SM: subacute myelofibrosis; rIFN-a-2b: recombinant interferon-a-2b. a May have had more than one indication. Fifty-four patients participated in the study over a period of 7.8 years between November 6, 1986 and September 1, 1995. A summary of their baseline and demographic characteristics appears in Table 2. The study population included 33 males and 21 females with a median age of 61 years (range, 22–77 years). The MPD variants represented were: AMM: 14 patients; PPV-MM: 6 patients; PET-MM: 2 patients; PV-MM: 17 patients; ET: 3 patients; PV: 8 patients; A-MPD: 3 patients; and SM: 1 patient. The duration of MPD before study entry was # 1 year in 9 patients and . 1 year in the remaining 45 patients. Conventional chemotherapy had failed in 29 patients, and 25 were previously untreated. The indications for rIFN-a-2b therapy were symptomatic splenomegaly (39 patients), thrombocythemia (24 patients), hyperleukocytosis (14 patients), and rIFN-a-2b in Myeloproliferative Disease/Gilbert 1209 TABLE 4 Summary of Mean Changes in Spleen Size and Laboratory Variables after the Induction Course of rIFN-a-2ba Spleenb Leukocytes Platelets Hematocrit PVSG diagnosis No. (%) Change (%) Range (%) Change (%) Range (%) Change (%) Range (%) Change (%) Range AMM PPV-MM PET-MM PV-MM ET PV A-MPD SM 14 6 2 17 3 8 3 1 217.42 219.4 20.1 233 56 273 7 0 275 to 18.8 241 to 0 28 to 18 288 to 118 0 to 1167 2400 to 0 271 to 114 — 20.19 225 235 259 250 248 222 266 218 to 1425.8 280 to 180 258 to 212 291 to 187 257 to 244 278 to 26 283 to 131 — 229 240 264 243 263 227 213 44 240.5 to 1157.7 282 to 14 265 to 262 268 to 22.6 282 to 236 276 to 1165 226 to 26 — 29.6 28 228 26 221 2 3.7 220 233 to 120 238 to 16 238 to 218 234 to 135 240 to 25 29 to 124 210 to 118 — rIFN-a-2b: recombinant interferon-a-2b; PVSG: Polcythemia Vera Study Group;. AMM: agnogenic myeloid metaplasia; PPV-MM: postpolycythemia vera myeloid metaplasia: PET-MM: postessential thrombocythemia myeloid metaplasia; PV-MM: active polycythemia vera with meyloid metaplasia; ET: essential thrombocythemia; PV: polycythemia rubra vera; A-MPD: atypical myeloproliferative disorder; SM: subacute myelofibrosis. a Values for variables after treatment with recombinant interferon-a-2b are at completion of induction course. b Total spleen was measured as the sum of the vertical and horizontal span. changes were 29% in the AMM patients, 40% in the PPV-MM patients, 64% in the PET-MM patients, 43% in the PV-MM patients, 63% in the ET patients, 27% in the PV patients, and 13% in the A-MPD patients. The SM patient experienced a 44% increase in mean platelet count. Mean hematocrit was reduced by 10%, 8%, 28%, 6%, 21%, and 20% in patients with AMM, PPV-MM, PET-MM, PV-MM, ET, and SM, respectively. The mean hematocrit increased by 2% and 4% in patients with PV and A-MPD, respectively. Response to rIFN-a-2b therapy also was analyzed according to the indication for treatment. Twenty-two patients with thrombocythemia at study entry responded, and platelet counts returned to normal in 18 of these 22 patients (82%). Of the 13 patients with leukocytosis, 12 (92%) responded, with the leukocytosis becoming normal in 3 patients and decreasing by a mean of 76% (range, 43–91%) in the other 9 patients. Splenomegaly decreased by a mean of 35% (range, 15– 88%) in 21 of 36 patients (58%). Of the remaining 15 patients, spleen size remained stable in 10 patients and increased in 5 patients. The clinical benefits of rIFN-a therapy are illustrated in the following example. A 38-year-old female patient who developed PV at age 32 years required phlebotomy for 2 years until experiencing a transformation to myeloid metaplasia with progressive splenomegaly and loss of her phlebotomy requirement. By the time the patient was age 35 years her spleen had enlarged into the right side of the abdomen and she was experiencing fatigue, early satiety, bilateral pedal edema, and abdominal fullness and discomfort. A course of hydroxyurea had no beneficial effect on spleen size and resulted in progressive anemia. Therapy with rIFN-a-2b was administered for 44 weeks, during which time there was a gradual reduction in splenomegaly. This was accompanied by correction of anemia, reduction of leukocyte and platelet counts to normal, and relief of all symptoms. The patient remained in remission for 1.5 years after the course of rIFN-a-2b therapy. Therapy and Unmaintained Response Durations Table 5 summarizes the durations of induction therapy and of response off therapy for two courses of the rIFN-a-2b regimen. Overall, the median duration of induction therapy was 34 weeks (range, 6 –129 weeks). Considering patients by diagnostic categories, median durations of induction therapy were as follows: AMM: 32 weeks; PPV-MM: 51 weeks; PET-MM: 20 weeks; PV-MM: 34 weeks; ET: 34 weeks; PV: 43 weeks; A-MPD: 12 weeks; and SM: 36 weeks. After discontinuation of induction therapy, 40 responding patients were monitored for unmaintained response. The median duration of unmaintained response among these patients was 60 weeks (range, 4 –249 weeks). By diagnostic group, median durations for unmaintained response were as follows: AMM: 46 weeks; PPV-MM: 35 weeks; PET-MM: 92 weeks; PVMM: 34 weeks; ET: 86 weeks; PV: 71 weeks; A-MPD: 173 weeks; and SM: 48 weeks. After the first off-therapy period, 24 patients exhibited increasing disease activity and were administered a second course of rIFN-a-2b. The median duration of the second course of treatment was 31 weeks (range, 4 –287 weeks). Considering patients by diagnostic categories, the median durations of the second 1210 CANCER September 15, 1998 / Volume 83 / Number 6 TABLE 5A Patient Outcomes and Duration of rIFN-a-2b Therapy: Induction Course Induction therapy Off therapy (unmaintained response) PVSG diagnosis No. of patients Weeksa Range No. of patients Weeksa Range AMM PPV-MM PET-MM PV-MM ET PV A-MPD SM Median duration 14 6 2 17 3 8 3 1 32 51 19.5 34 34 42.5 12 36 34 6–129 13–86 15–24 6–95 20–97 6–86 7–31 — 11 5 1 12 2 6 1 1 45.5 35 92 34 85.5 71 173 48 59.5 11–168 25–60 — 4–87 12–159 24–249 — — rIFN-a-2b: recombinant interferon-a-2b; PVSG: Polycythemia Vera Study Group; AMM: agnogenic myeloid metaplasia; PPV-MM: postpolycthemia vera myeloid metaplasia; PET-MM: postessential thrombocythemia myeloid metaplasia; PV-MM: active polycythemia vera with myeloid metaplasia; ET: essential thrombocythemia; PV: polycythemia rubra vera; A-MPD: atypical myeloproliferative disorder; SM: subacute myelofibrosis. a Values expressed represent median calculations. TABLE 5B Patient Outcomes and Duration of rIFN-a-2b Therapy: Second Course Second course Off therapy (unmaintained response) PVSG diagnosis No. of patients Weeksa Range No. of patients Weeksa Range AMM PPV-MM PET-MM PV-MM ET PV A-MPD SM Median duration 5 3 1 10 1 4 — — 69 14 21 29.5 134 33 — — 31.25 7–34 8–56 — 10–287 — 4–44 — — 5 3 1 9 — 2 — — 26 22 64 48 — 17.5 — — 26 6–81 16–35 — 15–149 — 15–20 — — rIFN-a-2b: recombinant interferon-a-2b; PVSG: Polycythemia Vera Study Group; AMM: agnogenic myeloid metaplasia; PPV-MM: postpolycythemia vera myeloid metaplasia; PET-MM: postessential thrombocythemia myeloid metaplasia; PV-MM: active polycythemia vera with myeloid metaplasia; ET: essential thrombocythemia; PV: polycythemia rubra vera; A-MPD: atypical myeloproliferative disorder; SM: subacute myelofibrosis. a Values expressed represent median calculations. course of therapy were as follows: AMM: 69 weeks; PPV-MM: 14 weeks; PET-MM: 21 weeks; PV-MM: 30 weeks; ET: 134 weeks; and PV: 33 weeks. Twenty patients were followed after discontinuation of the second course of treatment. Overall, these patients exhibited a median duration of unmaintained response of 26 weeks (range, 6 –149 weeks). Among individual treatment groups, the median durations of these second unmaintained responses were as follows: AMM: 26 weeks; PPV-MM: 22 weeks; PET-MM: 64 weeks; PV-MM: 48 weeks; and PV: 18 weeks. Fourteen patients received . 2 courses of rIFNa-2b therapy (overall range, 3– 41 weeks). These subsequent courses produced results similar to those demonstrated by the initial two courses of therapy. Overall, a total of 54 induction courses were administered, 24 second courses, 14 third courses, 11 fourth courses, 5 fifth courses, and 2 sixth courses. Survival At a median follow-up of 7.3 years, the median survival in this patient population had not been reached (Fig. 1). The survival rate at 8 years was 60%. Adverse Events Recombinant IFN-a-2b therapy generally was well tolerated. Adverse events reported by . 5% of patients included fever, chills, arthralgia, myalgia, fatigue, loss of appetite, alopecia, erythema and induration at the injection site, diarrhea, and neurologic symptoms. rIFN-a-2b in Myeloproliferative Disease/Gilbert FIGURE 1. Overall survival of 52 evaluable patients as of last follow-up (January 1998). The majority of side effects tended to be mild to moderate in severity, transient in nature, and rapidly reversible on dose modification. Initially, nearly all study participants experienced a flu-like syndrome characterized by pyrexia, chills, malaise, arthralgia, and myalgia. Tachyphylaxis to this adverse event generally occurred after 7–14 days of treatment. Adverse events, primarily a persistent flu-like syndrome and chronic fatigue, were responsible for five patients discontinuing study participation. DISCUSSION IFN-a is considered the standard of care in patients with chronic myelogenous leukemia (CML) who are ineligible for bone marrow transplantation.34 Complete hematologic remissions have been attained with rIFN-a therapy in 70 – 80% of patients with CML, and major cytogenetic responses have occurred in up to 40% of patients.35 Within the past 7 years, an increasing number of reports have been published suggesting a potential therapeutic role for rIFN-a therapy in the management of other variants of MPD. Several investigators have reported that rIFN-a treatment resulted in hematologic control accompanied by a reduced need for phlebotomy in a relatively large proportion of patients with PV.36 – 40 Other benefits of rIFN-a therapy noted in studies of PV patients include decreased splenomegaly,40 – 43 reduced risk of thrombosis, and remittance of intractable pruritus.36,39,44,45 Reduced platelet counts with relief of clinical symptoms also have been reported in series of patients with ET receiving rIFN-a therapy.38,46 – 49 Among patients with myeloid metaplasia, responses to rIFN-a therapy have been more variable.21,22,50 –52 Hematologic responses with primary rIFN-a induction therapy occur in approximately 75% of PV patients and 86% of ET pa- 1211 tients.53 These response rates compare favorably with those achievable with hydroxyurea. However, unlike conventional therapeutic approaches, including phlebotomy and chemotherapy, rIFN-a substantially controls splenomegaly, reduces the incidence of thrombohemorrhagic events, and may potentially alter the natural history of these diseases. Moreover, in a subset of patients, rIFN-a therapy produces long term responses of . 5 years.41 The results of the study presented in this article provide further evidence that rIFN-a-2b may be a useful agent in the management of PV, ET, and myeloid metaplasia. Evaluation of response according to the indication for treatment in the heterogeneous patient population that comprised this study clearly demonstrated that rIFN-a-2b can produce regression of splenomegaly, control of leukocyte and platelet counts, an increase in hematocrit among anemic patients, and a decreased need for phlebotomy in polycythemic patients (data not shown). Other standard-of-care modalities for MPD are associated with serious complications. Both radioactive phosphorus and cytotoxic drugs can induce leukemia or myelofibrotic transformation,33,53,54 whereas reduction of peripheral blood counts by phlebotomy may increase the risk of thrombotic accidents.33 In contrast to hydroxyurea, busulfan, and radioactive phosphorus, rIFN-a does not have any known leukemogenic or teratogenic effects. Nevertheless, rIFN-a therapy is not without toxicity. All patients receiving rIFN-a-2b in this study experienced a flu-like syndrome. Although this syndrome and other minor side effects associated with rIFN-a therapy may not be treatment-limiting, there is a potential for more serious adverse events to occur, particularly with long term therapy. The 39 patients who responded to therapy and who subsequently were withdrawn from rIFN-a-2b therapy add to previously reported evidence that rIFN-a produces durable treatment responses in patients with MPD after cessation of therapy.40,46,47 In the current study, the median duration of unmaintained response after the first course of rIFN-a-2b therapy was 60 weeks, but some patients were maintained successfully off treatment for $ 2 years. Moreover, no evidence was noted of patients becoming refractory to rIFN-a-2b therapy. Early reinstitution of rIFN-a-2b treatment in patients manifesting increased disease activity resulted in a return of hematologic control, whereas repeated courses of therapy cumulatively decreased splenomegaly. The ability to reinstitute treatment successfully with rIFN-a-2b in patients with recurrent disease also has been reported previously elsewhere40,47; however, to our knowledge this 1212 CANCER September 15, 1998 / Volume 83 / Number 6 report represents the longest follow-up reported to date (median, 7.3 years). The long term survival analysis presented in the current study demonstrates a median survival in excess of 8 years, although median survival has not been reached. This compares favorably with conventional modalities, but it is too early to draw definitive conclusions from this analysis. Studies conducted in patients with CML demonstrate that rIFN-a, unlike other drugs, suppresses the growth of cells bearing the abnormal karyotype and permits the reestablishment of a normal polyclonal bone marrow population in a significant number of patients.15,16 Cytogenetic studies on bone marrow specimens from patients with other variants of MPD treated with rIFN-a also show that this agent may inhibit the neoplastic clone selectively and allow reemergence of normal hematopoietic progenitor cells.42,43,51 Unfortunately, no cytogenetic data are available for any patients on this study. The fact that rIFN-a has produced unmaintained, long-standing disease remissions in patients with MPD suggests that rIFN-a has immunomodulatory activity in patients with MPD. Recombinant IFN-a has potent inhibitory effects on a variety of hematopoietic progenitor cells, including megakaryocyte progenitors, and this most likely is the primary mechanism by which rIFN-a therapy controls thrombocytosis and erythrocytosis. rIFN-a-2b appears to be a valuable agent in the management of MPD. It produces regression of splenomegaly, improvement in peripheral blood counts, and a reduction in the need for phlebotomy. Recombinant IFN-a-2b also is well tolerated and is capable of producing durable unmaintained responses. Based on this experience and other published reports, future studies with rIFN-a-2b are warranted. Therapy with rIFN-a-2b may be appropriate for early intervention in younger patients to halt disease progression before end-organ damage occurs. In addition, it may be a desirable treatment for elderly patients because of its minimal hematologic toxicity. Multicenter trials enrolling larger patient populations should be conducted to determine the optimal dosing regimen for this drug, the pattern of response to treatment, and whether any MPD phenotypes or patientrelated factors are predictive of success and sustained unmaintained response. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. REFERENCES 1. 2. Gilbert HS. Myeloproliferative disorders. Clin Geriatr Med 1985;1:773–93. Gilbert HS. Polycythemia vera and other polycythemic conditions. In: Rakel RE, editor. Conn’s current therapy. Philadelphia: W.B. Saunders, 1989:379 – 84. 19. Gilbert HS. Diagnosis and treatment of polycythemia vera, agnogenic myeloid metaplasia, and essential thrombocythemia. In: Wiernik P, Canellos GP, Kyle RA, Schiffer CA, editors. Neoplastic diseases of the blood. New York: Churchill Livingstone, 1991:123–36. Fialkow PJ, Jacobson RJ, Papayannopoulou T. 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