Cancer Treatment

Pegasys for Myelofibrosis

Interferon is effective in myeloproliferative disorders, which include myelofibrosis. Pegylated interferon is more convenient that interferon because it can be given weekly. However, in the one study in which marrow histology was examined, progression of myelofibrosis was not inhibited by pegylated interferon. Many patients with myelofibrosis are JAK2 positive and pegylated interferon has been shown to reduce Jak2 expression. However, the extent of evidence and number of publications is much smaller for myelofibrosis than for P. Vera and Essential Thrombocytosis. A recent (Nordic) guideline says: “JAK2-mutation is found in about half those patients with PMF. The findings of a steady decrease in the level of the JAK2-mutation in a large number of PV-patients during treatment with pegylated interferon α-2a supports the contention that IFN-treatment may influence the disease at the molecular level, at least in half of the patients (JAK2-positive). A prospective, randomised study of pegylated interferon versus HU in patients with PMF is warranted to clarify this issue”.

There is such an ongoing study: Pegasys® in Patients With Myeloproliferative Diseases, NCT00452023. The goal of this clinical research study is to see if Pegasys (IFN-alpha2a) can help to control the disease in patients with essential thrombocytosis (ET), polycythemia vera (PV), agnogenic myeloid metaplasia/myelofibrosis (AMM/MF), or Philadelphia chromosome-negative chronic myeloid leukemia (Ph-negative CML). The safety of this treatment will also be studied. Another study is: A Danish Study of Low-dose Interferon Alpha Versus Hydroxyurea in the Treatment of Philadelphia Chromosome Negative (Ph-)Chronic Myeloid Neoplasms - A National Randomized Prospective Study With Focus on Efficacy, Toxicity and Quality of Life”.

Pegasys remains investigational at this time.

 

 Verstovsek S, Lawhorn K, Giles F, et al. PEG-intron for myeloproliferative diseases: an update on ongoing phase II study. Blood. 2004;104:11. Abstract 1517.

Nordic MPD Study Group, http://www.legeforeningen.no/asset/38584/1/38584_1.pdf,

Hans Carl Hasselbalch, Myelofibrosis with myeloid metaplasia: The advanced phase of an untreated disseminated hematological cancer:
Time to change our therapeutic attitude with early upfront treatment? Leukemia Research Volume 33, Issue 1 , Pages 11-18, January 2009

 

Juvenile Myelomonocytic Leukemia

Smith FO, Loh ML. Myelodysplastic and myeloproliferative syndrome in children. In: Hoffman R, Benz EJ, Shattil SJ, Furie B, Silberstein LE, McGlave P, et al., editors. Hematology: basic principles and practice. 5th ed. Philadelphia (PA): Churchill Livingstone; 2008.

Juvenile myelomonocytic leukemia is a type of a myelodysplastic syndrome. The only treatment that has resulted in cures for JMML is a bone marrow transplant, with about a 50% survival rate. The risk of relapsing after transplant is high, and has been recorded as high as 50%. However, there is no other treatment that has a comparative cure rate and allogeneic transpalntation is supported by a number of studies as well as revieews and is recommended by PDQ.

 Taussig DC, Davies AJ, Cavenagh JD, Oakervee H, Syndercombe-Court D, Kelsey S, et al. Durable remissions of myelodysplastic syndrome and acute myeloid leukemia after reduced-intensity allografting. J Clin Oncol. 2003 Aug 15;21(16):3060-5.

Yoshimi A, Mohamed M, Bierings M, Urban C, Korthorf E, Zecca M, et al. Second allogeneic hematopoietic stem cell transplantation (HSCT) results in outcome similar to that of first HSCT for patients with juvenile myelomonocytic leukemia. Leukemia. 2007 Mar;21(3):556-60. Epub 2007 Feb 1.

Yusuf U, Frangoul HA, Gooley TA, Wooolfrey AE, Carpenter PA, Andrews RG, et al. Allogeneic bone marrow transplantation in children with myelodysplastic syndrome or juvenile myelomonocytic leukemia: the Seattle experience. Bone Marroe Transplant. 2004Apr;33(8)805-14.

Interferon for hypereosinophilic syndrome.

Chronic myeloproliferative disorders (CMPD) are classified according to the WHO classification of 2001 as polycythemia vera (PV), chronic idiopathic myelofibrosis (CIMF), essential thrombocythemia (ET), CMPD/unclassifiable (CMPD-U), chronic neutrophilic leukemia, and chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome, all to be delineated from BCR/ABL-positive chronic myeloid leukemia (CML). 

Hypereosinophilic syndromes (HES) and systemic mastocytosis (SMCD) are heterogeneous disorders with clinical symptoms from local and remote effects of excessive proliferation of eosinophils and mast cells, respectively. Interferon alpha (IFN-alpha), alone or in combination with other medications, can be a useful, and at times life-saving, treatment for patients with HES. Receptors for IFN-alpha are present on eosinophils, and clinical benefits are due to its effect on eosinophil proliferation, migration, activation, and survival. These effects are likely mediated through multiple pathways including, but not limited to, inhibition of eosinophil colony-forming cells, upregulation of IFN-gamma synthesis, and inhibition of production of eosinophil-active cytokines by T cells, mast cells, and mononuclear cells. A number of case reports showed that IFN-alpha has been life-saving for patients with intractable HES that were resistant to prednisone, hydroxyurea, and other agents. There are reports of combined use with hydroxyurea and prednisone. There are also reports of the use of peg-interferon.

Schnittger S, Schoch C.Modern diagnostics in chronic myeloproliferative diseases (CMPDs).Haferlach T, Kern W, Ann Hematol. 2004;83 Suppl 1:S59-61.

Butterfield JH.Interferon treatment for hypereosinophilic syndromes and systemic mastocytosis.Acta Haematol. 2005;114(1):26-40.

J. Butterfield PEG-Interferon after Interferon alfa-2b for Hypereosinophilic Syndrome
Journal of Allergy and Clinical Immunology, Volume 119, Issue 1, Pages S222-S222

Erytropoietin therapy for myelofibrosis

 Experience with recombinant human erythropoietin (rHuEPO) in the treatment of the anemia secondary to myelofibrosis with myeloid metaplasia (MMM) is limited.There are a number of reports of small numbers of patiens demonstrating responsiveness but also a recent report  which presents a picture of non-responsiveness of transfusion dependent myelofibrosis to erythropoietin therapy.
Initial studies failed to show significant improvements in hemoglobin levels upon administration of recombinant erythropoietin (rEpo). However, more recent investigations have demonstrated significant responses and decreased transfusion dependence in anemic patients with CIMF. The rEpo doses employed in those studies were in the range of 300–1,500 U/kg weekly. This finding underscores the current uncertainty about the optimal dose and schedule of rEpo in this disease. It is important to note that many patients with CIMF have normal serum erythropoietin levels, suggesting a potential lack of efficacy of rEpo in this setting [54]. Rodriguez et al. [ showed that a serum erythropoietin level <123 mU/ml was highly predictive of response to rEpo. This was recently corroborated by Cervantes et al. [53] in a study in which rEpo was given at an initial dose of 10,000 U three times per week to 20 patients with CIMF. Nine patients (45%) responded, including four who achieved normal hemoglobin levels. A serum erythropoietin level <125 mU/ml was associated with a favorable response to rEpo in the multivariate analysis. The combination of rEpo and thalidomide may represent a valid approach for patients with advanced CIMF
Future investigation will focus on stratification. Favorable cytogenetic findings was associated with response to erythropoietin therapy in one study.

In summary, there is sufficient evidence that Procrit raises Hb levels in many myelofibrosis patients. How to select patients is not entirely clear yet and at this time, a trial for effectivenesss is standard practice.It is not known whetehr it is a better long - term approach than periodic transfusions

Tsiara S, Kapsali H, Dimos GA, Chaidos A, Stoura M, Bourantas LK, Tzouvara E, Bourantas KL:
Treatment of anemia with recombinant human erythropoietin administration in patients with myelofibrosis, Archives of Hellenic Medicine 20 (3) : 281-285 (May 2003)

S.N. Tsiara, A. Chaidos, L.K. Bourantas, H.D. Kapsali, K.L. BourantasRecombinant Human Erythropoietin for the Treatment of Anaemia in Patients with Chronic Idiopathic Myelofibrosis Heamatoloica Vol. 117, No. 3, 2007  

EAuthor  Huang, J. Lasho, T.L. Li, C.Y. Pardanani, A.D. Mesa, R.A. Tefferi, A. 
rythropoietin Therapy Does Not Benefit Transfusion-Dependent Primary Myelofibrosis Patients and Treatment Response Is Infrequent with a Baseline Hemoglobin Level &gt;or= 10 g/dL
 BLOOD 2007, VOL 110;  pages 3555 

Tefferi A, Lasho TL, Schwager SM et al. The JAK2(V617F) tyrosine kinase mutation in myelofibrosis with myeloid metaplasia: lineage specificity and clinical correlates. Br J Haematol 2005;131:320–328

JAK2 for diagnosis

Lay Summary: JAK2 testing can now be performed for a diagnosis of a myeloproliferative disorder.  This is now an acceptable approach to diagnosing myeloproliferative disorders.

In early 2005, several groups of investigators reported a somatic acquired point mutation in the JAK2 (Janus kinase 2) protein in the blood and bone marrow of patients with BCR/ABL-negative chronic myeloproliferative disorders. JAK2 is a tyrosine kinase which plays an important role in normal hematopoietic growth factor signaling, and the mutation results in activation of the kinase and deregulated intracellular signaling with cell proliferation that is independent of normal growth factor control.

Using sensitive assays, the JAK2 mutation can be detected in approximately 90-95% of cases of polycythemia vera, 50-70% of patients with essential thrombocythemia, and 40-50% of cases of idiopathic myelofibrosis. The mutation has also been described in rare cases of myelodysplastic syndromes, acute myeloid leukemia, systemic mastocytosis and hypereosinophilic syndrome. It is specific for diagnosis of a clonal myeloid lineage proliferative disorder. The mutation has not been described in BCR/ABL-positive chronic myeloid leukemia, any acute or chronic lymphoid disorders, any healthy persons, or any patient with secondary polycythemia or a reactive blood count elevation. The JAK2 test promises to be very useful in distinguishing between clonal myeloproliferative disorders and reactive cellular proliferations.

Mary F. McMullin, John T. Reilly, Peter Campbell, David Bareford, Anthony R. Green, Claire N. Harrison, Eibhlin Conneally, on behalf of the National Cancer Research Institute, Myeloproliferative Disorder Subgroup, Kate Ryan, on behalf of the British Committee for Standards in Haematology (2007)  Amendment to the guideline for diagnosis and investigation of polycythaemia/erythrocytosis
British Journal of Haematology 138 (6), 821–822.

James, C., Ugo, V., Le Couedic, J.P., Staerk, J., Delhommeau, F., Lacout, C., Garcon, L., Raslova, H., Berger, R., Bennaceur-Griscelli, A., Villeval, J.L., Constantinescu, S.N., Casadevall, N. & Vainchenker, W. (2005) A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature, 434, 1144–1148.

McMullin, M.F., Bareford, D., Campbell, P., Green, A.R., Harrison, C., Hunt, B., Oscier, D., Polkey, M.I., Reilly, J.T., Rosenthal, E., Ryan, K., Pearson, T.C. & Wilkins, B., General Haematology Task Force of the British Committee for Standards in Haematology. (2005) Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. British Journal of Haematology, 130, 174–195.

Pegasys for P. Vera and Essential Thrombosis.

Intron A is a well established treatment for essential thrombocythemia (ET) and P. Vera, especially effective for control of pruritis. Interferon-(IFN) suppresses growth of multipotent hematopoietic progenitor cells. No leukemogenic risk has been reported. No randomized trials have been published. In the Italian guidelines for treatment of ET 15 studies have been summarized, including 292 patients. Complete normalization of platelet counts was achieved in 54% of the patients.

Pegasys is a form of pegulated interferonPegylated IFN given weekly has been shown to have equal efficacy as IFN given trice weekly. The most recent guideline (Nordic MPD Study Group) recommendation is: " Recommendation: IFN-α is theoretically superior for treating PV as it is effective in controlling proliferation of all cell lineages and there is no risk of leukemogenesis. Molecular remissions can be
acheived with IFN. It is most likely to be tolerated in patients below 60 years for whom it is
recommended. Pegylated forms of IFN seem equally effective as conventional IFN.
Grade B recommendation, evidence level III.

In summary, recent data suggest that pegylated INF alfa-2a (Pegasys; Hoffman-La Roche, Inc, Nutley, NJ) is likely to be as effective as IFN.

Barosi G, Lupo L, Rosti V. Management of myeloproliferative neoplasms: from academic guidelines to clinical practice.Curr Hematol Malig Rep. 2012 Mar;7(1):50-6.

McMullin MF, Bareford D, Campbell P, et al.: Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol 130 (2): 174-95, 2005. 

Campbell PJ, Green AR: The myeloproliferative disorders. N Engl J Med 355 (23): 2452-66, 2006. 
Finazzi G, Barbui T: How I treat patients with polycythemia vera. Blood 109 (12): 5104-11, 2007.  [PUBMED Abstract]

Kiladjian JJ, Cassinat B, Chevret S, et al.: Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 112 (8): 3065-72, 2008

 Cortes, MD, Deborah Thomas, MD, Guillermo Garcia-Manero, MD, Alessandra Ferrajoli, MD, Stefan Faderl, MD, Mary Ann Richie, Miloslav Beran, MD, PhD, DVM, Francis Giles, MD, Srdan Verstovsek, MD, PhD Final Result of a Phase 2 Study PEG-IFN--2b therapy in BCR-ABL-negative myeloproliferative disorders Cancer Volume 110 Issue 9, Pages 2012 - 2018

 http://www.sfhem.se/filarkiv/files/vardprogram/NMPDGuidelines2007.pdf

 Samuelsson J, Mutschler M, Birgegård G, Gram-Hansen P, Björkholm M, Pahl HL Limited effects on JAK2 mutational status after pegylated interferon alpha-2b therapy in polycythemia vera and essential thrombocythemia.Haematologica. 2006 Sep;91(9):1281-2.

ASCO 2011, 461 High Rates of Molecular Response After Long-Term Follow-up of Patients with Advanced Essential Thrombocythemia (ET) or Polycythemia Vera (PV) Treated with Pegylated Interferon-ALFA-2A (PEG-IFN-α-2A; PEGASYS )

Allogeneic SCT for Myelofibrosis

Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloproliferative disorder characterized by bone marrow fibrosis and extramedullary hematopoiesis. Several nonrandomized studies have indicated that allogeneic SCT for patients under the age of 55 is effective in prolonging survival in more than 50% of cases and in possibly curing the disease. A 1999 Consensus conference recommended that patients with the most severe prognosis are candidates.

Several studies suggest that unrelated allogeneic transplants with full conditioning are too toxic to be routinely advised. Allo-SCT is the only available therapy for patients with CIMF with potential to eliminate bone marrow fibrosis and possibly cure patients. Nonetheless, the use of fully myeloablative conditioning regimens has been associated with high morbidity and mortality. In particular, the age of patients undergoing allo-SCT proved to be a critical prognostic factor in one study, in which 14% of patients older than 45 years at the time of transplantation survived beyond 5 years of follow-up.

Recently, a retrospective analysis of the outcomes of 320 patients with CIMF receiving allo-SCT between 1989 and 2002 was published. Most patients received ablative conditioning with either total body irradiation (TBI) (n = 117) or busulphan (n = 150) and cyclophosphamide. Bone marrow was the graft source in 208 patients. HLA-identical sibling donors were used in 170 transplants, 117 were from a matched unrelated donor (MUD), and 33 were from an alternative related donor. The 100-day mortality rates were 22% after sibling transplants, 42% after MUD transplants, and 27% after alternative family donor transplants. Corresponding 5-year overall survival rates were 39%, 31%, and 31%, respectively. Multivariate analysis of 215 adult recipients of myeloablative transplants revealed that having an HLA-identical sibling donor, Karnofsky performance score =90%, younger age, more recent date of transplantation, and absence of blasts in peripheral blood prior to transplantation correlated with better survival. Eighteen patients with all of these factors had a 5-year probability of survival of 81%. Although the ideal conditioning regimen is yet to be defined, cyclophosphamide plus busulphan (with busulphan doses adjusted to achieve targeted plasma levels) resulted in better outcomes when compared with TBI-based regimens.

The introduction of reduced-intensity conditioning (RIC) nonmyeloablative regimens may be particularly applicable in CIMF. The main complication of allo-SCT in patients older than 45 years is transplant-related mortality rather than relapse. The patients in this age group represent the bulk of patients with CIMF, and employing low-intensity conditioning may improve their probability of survival. Sustained engraftment and durable responses have been reported in several case reports involving patients with advanced-stage CIMF who receive fluda-rabine-based RIC regimens. This appears to be a more promising option for these patients.

C. Arana-Yi, A. Quintas-Cardama, F. Giles, D. Thomas, A. Carrasco-Yalan, J. Cortes, H. Kantarjian, and S. Verstovsek
Advances in the Therapy of Chronic Idiopathic Myelofibrosis
Oncologist, September 1, 2006; 11(8): 929 - 943.

Tefferi, G. Barosi, R. A. Mesa, F. Cervantes, H. J. Deeg, J. T. Reilly, S. Verstovsek, B. Dupriez, R. T. Silver, O. Odenike, J. Cortes, M. Wadleigh, L. A. Solberg Jr, J. K. Camoriano, H. Gisslinger, P. Noel, J. Thiele, J. W. Vardiman, R. Hoffman, N. C. P. Cross, D. G. Gilliland, and H. Kantarjian
International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT)
Blood, September 1, 2006; 108(5): 1497 - 1503.

G. Rondelli, G. Barosi, A. Bacigalupo, J. T. Prchal, U. Popat, E. P. Alessandrino, J. L. Spivak, B. D. Smith, H. G. Klingemann, S. Fruchtman, and R. Hoffman
Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia
Blood, May 15, 2005; 105(10): 4115 - 4119.

Interferon for Myeloproliferative disorders

The myeloproliferative disorders consist of polycythemia vera, chronic myelogenous leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia. All these disorders are thought to result from a hematopoietic stem cell lesion.

Interferon alfa is effective in suppressing bone marrow function in chronic myeloproliferative disorders, but this treatment requires multiple weekly injections. Pegylated interferon, on the other hand, can be given weekly. Several groups reported on the results of phase 2 trials of pegylated interferon alfa 2b in essential thrombocytosis and polycythemia vera with generally concordant results.Satisfactory platelet count reduction was achieved with 3 to 6 months of therapy in approximately 70% of patients, but the drug had to be discontinued in 15% to 52% of them because of side effects. In the one study in which marrow histology was examined, progression of myelofibrosis was not inhibited by pegylated interferon. The number of studies and quality of evidence meets Caremark criteria for approval. The therapy is not investigational and it is medically necessary.

Gugliotta L, Bulgarelli S, Tienghi A, et al. Bone marrow biopsy and aspirate evaluation in 90 patients with essential thrombocythemia treated with peg interferon alpha-2b. Preliminary results. Blood. 2004;104:11. Abstract 1523.

Samuelsson J, Hasselbalch H, Bruserud O, et al. A phase II trial of pegylated interferon alpha-2b in polycythemia vera and essential thrombocythemia: clinical responses, effects on PRV-1 expression and impact on quality of life. Blood. 2004;104:11. Abstract 1518.

Langer C, Lengfelder E, Thiele J, et al. Treatment with pegylated interferon alpha (Pegintron) for high-risk essential thrombocythemia: results of a phase II study. Blood. 2004;104:11. Abstract 1522.

Verstovsek S, Lawhorn K, Giles F, et al. PEG-intron for myeloproliferative diseases: an update on ongoing phase II study. Blood. 2004;104:11. Abstract 1517.