Cancer Treatment

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 reprots 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 Hblevels 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

Revlimid for myelofibrosis

There are now 2 similarly designed but separate phase 2 studies involving single-agent lenalidomide (CC-5013, Revlimid) in a total of 68 patients with symptomatic myelofibrosis with myeloid metaplasia (MMM). Protocol treatment consisted of oral lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 100 x 109/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 additional months, in case of response. Overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. Response in anemia was deemed impressive in 8 patients whose hemoglobin level normalized from a baseline of either transfusion dependency or hemoglobin level lower than 100 g/L. The authors concluded that lenalidomide engenders an intriguing treatment activity in a subset of patients with MMM that includes an unprecedented effect on peripheral blood and bone marrow abnormalities.

Ayalew Tefferi, Jorge Cortes, Srdan Verstovsek, Ruben A. Mesa, Deborah Thomas, Terra L. Lasho, William J. Hogan, Mark R. Litzow, Jacob B. Allred, Dan Jones, Catriona Byrne, Jerome B. Zeldis, Rhett P. Ketterling, Rebecca F. McClure, Francis Giles, and Hagop M. Kantarjian
Lenalidomide therapy in myelofibrosis with myeloid metaplasia
Blood 108: 1158-1164;

Tefferi, Ayalew
Pathogenesis of Myelofibrosis With Myeloid Metaplasia
J Clin Oncol 2005 23: 8520-8530
 

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.

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 [37].

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 fo evidence mmets Caremark criteria for apporval. 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.