Supportive Care and Hematologic Malignancies

Posted on January 21st, 2008 by

Supportive Care and Hematologic Malignancies: A Report from the 2007 American Society of Hematology (ASH) Meeting

Introduction

At the 2007 meeting of the American Society of Hematology (ASH) the most interesting supportive care studies involved second generation thrombopoetin-like agents that should ultimately improve the treatment of thrombocytopenia.

Thrombocytopenia

Thrombocytopenia is a major cause of morbidity and mortality in patients receiving chemotherapy for malignancy. Thrombopoetin (TPO) or thrombopoetin-like drugs have had limited success for the treatment of thrombocytopenia, primarily due to antibody production. Currently, oprelvekin is the only FDA-approved drug for treating or preventing thrombocytopenia; however, it has not been very widely used.

PEG-rHuMGDF (pegylated recombinant human megakaryocyte Growth and Development Factor) has been in clinical trials for a decade and until recently there has been little evidence that this agent significantly improves platelet recovery in patients receiving chemotherapy. Recently researchers from Memorial Sloan-Kettering Cancer center have reported that the administration of PEG-rHuMGDF may have improved the survival of patients with refractory diffuse large cell lymphoma (DLCL) treated with ICE (ifosfamide, carboplatin and etoposide) chemotherapy. The details of this study were reported in the November, 2007 issue of Annals of Oncology.1

This study was a randomized, double-blind, placebo controlled Phase I/II trial in 41 patients with refractory or relapsed DLCL who were treated with ICE. These authors reported that patients receiving PEG-rHuMGDF had less grade IV thrombocytopenia and received fewer platelet transfusions than the control group. They also reported that the dose-intensity of ICE was better in the PEG-rHuMGDF group than in the control group. Patients in the PEG-rHuMGDF group received 75% of protocol dosing of ICE compared to 42% in the control group. With an 8.5 year follow-up, the overall survival of patients in the PEG-rHuMGDF group was 59% versus 31% in the control group. This was a study carried out several years ago and there have been no recent trials of PEG-rHuMGDF reported. The importance of this study is to stimulate more interest in evaluating the new generation of TPO drugs, such as romiplostim in patients with chemotherapy-induced thrombocytopenia.

Second Generation TPO-Like Agents

More recently, research has focused on a second generation of TPO-like agents that have been developed by identifying peptides that bind the TPO receptor with high affinity. Because they bear no structural resemblance to TPO, but still bind and activate the TPO receptor, these compounds are called TPO mimetics. Several peptides have been identified, and they have been further modified to both prolong their half-life in plasma as well as to increase their efficiency in activating the TPO receptor. The theoretical advantage of these compounds over standard recombinant TPO is that they bear little structural similarity with native TPO, and should not trigger auto-immune anti-TPO antibodies like PEG-MDGF.

Romiplostim (AMG531)

Romiplostim is the most developed pharmaceutical in the peptide TPO mimetic category. It is composed of several copies of the TPO receptor-binding peptide spliced into an IgG1 Fc fragment. This peptide mimetic competes with TPO for binding to the TPO receptor, and activates the receptor in an identical fashion to endogenous TPO. When administered subcutaneously to humans, romiplostim produces a dose-dependent increase in platelets counts and has been effective in treating thrombocytopenia associated with immune (idiopathic) thrombocytopenia purpura (ITP) and myelodysplastic syndromes (MDS).

Romiplostim for Chronic ITP: Chronic ITP is a disease associated with decreased megakaryocytes and decreased TPO responses. Bussel et al. conducted a clinical trial published in the New England Journal of Medicine evaluating romiplostim in the treatment of ITP among patients who had received prior treatment.2 Romiplostim demonstrated platelet responses in 68% of these patients with no major adverse events reported. At ASH 2006, the long-term safety profile of romiplostim was reported.3 These authors reported the outcome of 36 ITP patients who continued to receive weekly subcutaneous injections of the study drug. Twenty-nine patients received romiplostim for longer than 48 weeks. Eighty-six percent of patients had a platelet response defined as at least double the baseline platelet count, and at least 50,000/µl. The majority of the responding patients had platelet counts greater than 150,000/µl. The most frequent adverse events were headache, upper respiratory tract infection, and fatigue. Overall, the results showed that long-term treatment with this TPO mimetic might be a viable therapeutic option for patients with refractory ITP.

At ASH 2007, researchers from several U.S. and European centers presented the results of a randomized trial of romiplostim in patients with chronic ITP who had been splenectomized.4 Sixty-three patients with chronic ITP were randomized on a 2:1 basis to receive romiplostim or placebo for 24 weeks. Most of the patients had their disease for 8-9 years, were splenectomized and had platelet counts less than 30,000. The overall response rate was 79% in the romiplostim group and 0% in the placebo group. Thirty-eight percent of the responses were durable. Patients in the romiplostim group were more likely to have reduced therapies for chronic ITP.

Researchers also reported the effects of romiplostim in patients with chronic ITP who had not been splenectomized.5 Sixty-two patients with chronic ITP who had not been splenectomized were randomized on a 2:1 basis to receive romiplostim or placebo. A durable platelet response (>50,000 for more than 6 weeks) was achieved in 61% of patients receiving romiplostim and 4.8% of patients receiving placebo. Overall response rate (durable or transient response) was observed in 88% of patients receiving romiplostim and 14% of patients receiving placebo. Romiplostim also reduced the use of rescue medications compared to placebo and was considered to be well tolerated.

The effects of long-term dosing of romiplostim in patients with chronic ITP were also reported.6 This study enrolled 136 patients with chronic ITP with the longest treatment duration being 122 weeks. Baseline platelet counts in this group of patients averaged 18,000 and 60% of patients had undergone spleenectomy. The most frequent adverse events were headache, contusion, fatigue, diarrhea, epistaxis, pharyngitis and arthralgia. Eleven patients were deemed to have serious side effects associated with romiplostim, including three withdrawals from study due to vaginal hemorrhage, increased reticulin in the bone marrow and a case of monoclonal gammopathy. There was no association between symptoms and increased duration of therapy with romiplostim. Only one patient developed antibodies to romiplostim, which was not associated with resistance to the thrombopoietic effect of romiplostim. A platelet response was achieved by 82% of patients as measured by increases to >50,000 and doubling of baseline platelet counts. First responses occurred at a median of two doses of romiplostim. Thirteen of 30 patients receiving concurrent therapy had such therapy discontinued after treatment with romiplostim. These authors concluded that “individualized weekly doses of romiplostim provide a therapeutic option for long-term treatment of chronic ITP.”

Patients with chronic ITP receiving romiplostim were also less likely to receive immunoglobulin (IVIG or Anti D) than patients receiving placebo.7 This study evaluated the use of immunoglobulin, IVIG or Anti D, as rescue medications for patients receiving romiplostim or placebo in a large randomized trial. The probability of immunoglobin treatment was 50% in the control group and 10% in the romiplostim group. These authors concluded that romiplostim treatment “was associated with significantly reduced immunoglobulin use in both splenectomized and non-splenectomized patient with chronic ITP.”

Romiplostim for Myelodysplastic Syndromes

At ASH 2007, researchers affiliated with The AMG 531 Myelodysplastic Syndrome Study Group reported that romiplostim can reduce bleeding and transfusion events in patients with MDS.8 The study of romiplostim for the treatment of thrombocytopenia related to MDS was presented by Dr. Kantarjian from the MD Anderson Cancer Center. This was a Phase I/II study in patients with low-risk MDS with baseline platelet levels below 50,000. They enrolled 44 patients, of whom, 40 were treated on an extended basis with 16 patients remaining on study. Forty-one percent of patients achieved a platelet response lasting at least eight weeks. Responses were similar between those with platelet counts above or below 20,000. The mean duration of platelet responses was 23 weeks. Romiplostim appeared to be well tolerated. These authors concluded that bleeding and transfusion events can be reduced in thrombocytopenic low-risk MDS patients.

Eltrombopag for Chronic ITP

Eltrombopag is an oral non-peptide thrombopoetin receptor agonist with a low immunogenic potential. Results from a previously conducted phase I trial including 73 subjects demonstrated that eltrombopag increases the platelet counts in healthy volunteers in a dose-dependent fashion. The results of a Phase II placebo-controlled double-blind trial further evaluating eltrombopag were presented at ASH 2006. In this study, the platelet counts of 117 patients with chronic ITP were analyzed after six weeks of therapy with 30, 50, or 75 mg of daily eltrombopag. Notably, all patients in this trial had at least one prior form of therapy, and the patients were allowed to continue prednisone therapy while they received the test drug. Approximately 75% of the ITP patients exposed to the two higher daily doses of eltrombopag for six weeks had a median platelet count greater than 50,000/µl, and 40% of the patients had a platelet count greater than 200,000/µl. In contrast, patients receiving placebo had a mean platelet count of 16,000/µl. Headache was the most common adverse event, and the remaining adverse events were mild. These data have subsequently been published in the New England Journal of Medicine.9

At ASH 2007, researchers affiliated with an international study have reported that long-term use of eltrombopag is safe and effective for the treatment of chronic ITP.10 The EXTEND study involved 94 patients who had been previously enrolled on clinical trials of eltrombopag. The goal was to evaluate the long-term effects of chronic administration of a titrated dose of eltrombopag. The starting dose of eltrombopag was 50/mg/day with the goal of maintaining platelet levels at 50,000. Ninety patients were evaluable for initial treatment, 17 were tapering other therapies for ITP, 46 were in the process of titrating eltrombopag to maintain platelet levels and 27 were in the long-term maintenance phase of treatment. Treatment duration averaged 151 days (2-333 days). Forty-three percent of patients in this trial had platelet levels <15,000 and 63% had evidence of bleeding. Seventy-three percent achieved a platelet count of 50,000 or greater. Most adverse events were described as mild. A separate presentation was made summarizing the safety of eltrombopag in ITP patients participating in four randomized trials.11 These data suggest that eltrombopag is effective for the long-term treatment of patients with chronic ITP.

Anemia

Erythropoietic stimulating agents (ESA) have been much in the news lately, driven by reports of lack of efficacy in non-approved settings such as anemia of cancer and potential safety signal proposed by recent clinical trails and some biological experiments. There is concern that targeting higher hemoglobin levels may increase the risk of recurrence in patients with head and neck cancer, non-small cell lung cancer and breast cancer. There is much debate on both sides of the topic. The major concern is that targeting higher hemoglobin levels may have led to an increase in certain cancers and an increase in thrombo-embolic complications. Some of these issues were addressed by researchers from several U.S. medical centers who updated the clinical practice guidelines for the use of epoetin alfa and darbepoetin alfa. These guidelines have been approved by the American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO) and were published in Blood in January of 2008.12

ESAs in Patients with CML: The use of ESAs have been associated with an increased relapse rate in single studies of patients with breast cancer, head and neck cancer and lung cancer. However, most studies have not shown an increase in relapse rates or decreased survivals in patients with cancer receiving ESAs after chemotherapy. An earlier study from MD Anderson reported that ESA administration could correct the anemia associated with treating patients with chronic myeloid leukemia (CML).13 This study also suggested that patients with anemia had a worse outcome than patients without anemia.

At ASH 2007 researchers from the MD Anderson Cancer Center reported that the use of Epogen or Aranesp did not affect survival of patients with chronic myeloid leukemia (CML) treated with Gleevec.14 This analysis included 306 previously untreated patients and 259 who were treated with interferon prior to receiving Gleevec. The following table summarizes overall survival (OS) and event-free survival (EFS) outcomes of these two groups of patients treated with Gleevec.

Interferon Failures (%)

Frontline Gleevec (%)

ESA Use

OS

EFS

OS

EFS

No

84

75

92

84

Yes

82

68

89

85

These authors concluded that “there is no evidence that the use of ESA to manage anemia associated with imatinib therapy in pts with CML in chronic phase adversely affects long term overall survival or event-free survival.” These data would suggest that Epogen and Aranesp are safe to give to anemic patients with CML in chronic phase receiving Gleevec without fear of increasing the rate of recurrent disease.

Summary

The major supportive care studies at ASH 2007 involved the demonstrated effectiveness of two TPO-like agents, romiplostim and eltrombopag, in treating thrombocytopenia in patients with chronic ITP and MDS.

References:


1 Moskowitz CH, Hamlin PA, Gabrilove J, et al. Manintaing the dose intensity of ICE chemotherapy with a thrombopoietic agent, PEG-rHuMGDF, may confer a survival advantage in relapsed and refractory aggressive non-Hodgkin Lymphoma. Annals of Oncology. 2007;18:1842-1850.

2 Bussel JB, Kuter DJ, Phil D, et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP.New England Journal of Medicine 2006; 355:1672-1681.

3 Kuter D, Bussel, J, George J, et al. Long-term dosing of AMG 531 in thrombocytopenic patients with immune thrombocytopenic purpura: 48-week update. Blood. 2006; 108:168, Abstract #476.

4 Gersheimer TB, Pullarkat V, Senecal FM, et al. Evaluation of AMG 531 efficacy in splenectomized patients with chronic immune thrombocytopenic purpura (ITP) in a randomized placebo-controlled phase 3 study. Blood 2007;110:8a, abstract number 2. Blood 2007;110:173a, abstract number 565.

5 Kuter DJ, Bussel JB, Senecal FM, et al. Evaluation of AMG 531 in nonsplenectomized patients with chronic immune thrombocytopenic purpura in a randomized placebo-controlled phase 3 study.

6 Bussel JB, Kuter DJ, de Wolf JThM, et al. Long-term dosing of AMG 531 in thrombocytopenic patients with immune thrombocytopenic purpura: 2-year update. Blood 2007;110:174a, abstract number 568.

7 Pullarkat V, Gersheimer TB, de Wolf JThM, et al. Reduction in immunoglobulin (VIG or Anti D) use in patients with chronic immune thrombocytopenic purpura (ITP) receiving AMG 531. Blood 2007;110:313a, abstract number 1034.

8 Kantarjian H, Fenaux P, Sekeres MA, et al. Phase ½ study of AMG-531 in thrombocytopenic patients (pts) with low-risk myelodysplastic syndrome (MDS): Update including extended treatment. Blood 2007;110:81a, abstract number 250.

9 Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. New England Journal of Medicine 2007;357:2237-2247.

10 Bussel JB, Cheng G, Kovaleva L, et al. Long-term safety and efficacy of oral eltrombopag for the treatment of subjects with idopathic thrombocytopenic purpura (ITP): Preliminary data from the EXTEND Study. Blood. 2007;110:174a, abstract 566.

11 Bussel JB, McHutchison J, Provan D, et al. Safety of eltrombopag, an oral non-peptide platelet growth factor, in the treatment of thrombocytopenia: Results of four randomized, placebo-controlled studies. Blood. 2007;110:391a, abstract 1299.

12 Rizzo JD, Somerfield MR, Hagerty KL, et al. American Society of Hematology/American Society of Clinical Oncology 2007 clinical practice guideline update on the use of epoetin and darbepoetin. Blood 2007;26:132-149.

13 Cortes J, O’Brien S, Quintas A, et al. Erythropoietin is effective in improving the anemia induced by imatinib mesylate therapy in patients with chronic myeloid leukemia in chronic phase. Cancer 2004;100:2396-2402.

14 Alvarado Y, Kantarjian H, Verma D, et al. Long-term prognostic impact of the use of erythropoiesis-stimulating agents (ESA) in patients (pts) with chronic myeloid leukemia (CML) treated with imatinib. Blood 2007;110:869a,abstract number 2959.

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