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
 

Intravenous gamma globulin for pure red cell aplasia

Pure red cell aplasia (PRCA) describes a condition in which RBC precursors in bone marrow are nearly absent, while megakaryocytes and WBC precursors are usually present at normal levels. In 1922, Kaznelson recognized that this condition was a different entity than aplastic anemia. Pure red cell aplasia exists in several forms, and the most common form is an acute self-limited condition. Acquired pure red cell aplasia is often chronic and is associated with underlying disorders such as thymomas and autoimmune diseases.

The acquired chronic form of pure red cell aplasia is associated with thymomas and autoimmune disorders. Damage to erythroid progenitors or precursor cells appears to be immune and T-cell mediated. It is tempting to sue IVIG to regulate immune function so as to affect immunologic function. There is sufficient evidence that this is effective and a recent guideline recommends use of IVIG for red cell aplasia. Specific recommendations for routine use of IVIG were made for 7 conditions including acquired red cell aplasia (others were: acquired hypogammaglobulinemia (secondary to malignancy); fetal-neonatal alloimmune thrombocytopenia; hemolytic disease of the newborn; HIV-associated thrombocytopenia; idiopathic thrombocytopenic purpura; and posttransfusion purpura.)

Most studies that show resposne use "high-dose".  Total dose is administered IV but is graduated with low doses initially to monitor for anaphylaxis and other complications. Therefore, doses mentioned in package insert should be followed. Lower dosages/d but extended over 4 d are indicated in patients with fluid overload.  Adult Dose Not to exceed 2 g/kg IV over 4 d
Zimmer J, Regele D, de la Salle H. Pure red-cell aplasia. N Engl J Med. Jun 24 1999;340(25):2004-5.

D . Anderson , K . Ali , V . Blanchette , M . Brouwers , S . Couban , P . Radmoor , L . Huebsch , H . Hume , A . McLeod , R . Meyer Guidelines on the Use of Intravenous Immune Globulin for Hematologic Conditions .  Transfusion Medicine Reviews , Volume 21 , Pages S9 - S56 2007

Gleevec for liver cancer

While there is resonable theoretical basis for the use of Gleevec for HCC, there is littel supporting clicnial data. A recent pahse II study revealed that fifteen patients, median age 58 years, were enrolled and treated with imatinib. Most, or 7, patients had hepatitis B virus as a risk factor for HCC, followed by hepatitis C virus in 3 patients. Metastatic disease (American Joint Committee on Cancer stage IV) was noted in 13 patients and locally advanced (stage III) in the remainder. The median dose-level of imatinib was 500 mg/d. Two patients had stable disease lasting more than 2 months. The remainder progressed within 2 months of initiation of imatinib. No grade 3 or 4 hematologic toxicity was observed. Two patients had grade 3 elevated liver function tests during treatment; otherwise, there was no other grade 3 or 4 nonhematologic toxicity noted.
Although toxicities were tolerable, imatinib as a monotherapy for the treatment of unresectable HCC has little, if any, significant efficacy.

While EGFR analysis may allow selecting patients who will respond better, this remains to be proven.

Lin, Albert Y. MD et al, Phase II Study of Imatinib in Unresectable Hepatocellular Carcinoma. American Journal of Clinical Oncology. 31(1):84-88, February 2008.

S D Ryder Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults Gut 2003;52:iii1

Neupogen to allow ribavirin and interferon treatment of Hepatitits C

Pegylated interferons have been associated with a greater decrease in absolute neutrophil counts than standard interferons, requiring dose reduction secondary to neutropenia in 18-20% of treated patients. While neutropeniais common, rarely is the neutropenia severeenough to warrant permanent discontinuationof therapy. If the neutrophil count drops below0.75 x 109 / L, the pegylated interferon doseshould be reduced by 50%. If the neutrophilcount falls below 0.50 x 109 / L, therapy shouldbe discontinued. Neutrophil counts usuallyreturn to pretreatment levels within four weeksof stopping therapy. Based upon the concern ofneutropenia, many physicians have advocatedthe use of granulocyte-colony stimulating factor(G-CSF) at a dose of up to 300 ug subcutaneouslyper week. Currently, there are no clinical trials to demonstrate the effectiveness of G-CSF although clinical experience does support its efficacy in certain situations. Guidelines state: "Routine use of growth factors, such as epoetin and granulocyte colony-stimulating factor (G-CSF) was considered but not recommended". At this time there is an absence of data supporting the preemptive use of growth factors in this patient population.

In this case, the use is not routine but in order to enable therapy for hepatitis C.Many patients with chronic hepatitis C (HCV) infection undergoing treatment with pegylated interferon-alpha (PEG-IFN-alpha) and ribavirin develop neutropenia requiring dose reduction or granulocyte colony-stimulating factor (G-CSF) supplement. The VA wrote guidelines supporting its use under some conditions, but leukopenia has to be demonstrated first on interferon/ribavirin and dose reduction is to be pursued before Meupogen is used. In a recent database of patients who completed treatment for chronic HCV infection between 2003 and 2006, patients with absolute neutrophil counts below 1000 cells/microL were initiated on G-CSF (G-CSF group) while a matching group of patients who received anti-HCV treatment without developing neutropenia were used as a control group (non-G-CSF group). Patients on the G-CSF arm were divided into two subgroups based on the timing of G-CSF administration relative to PEG-IFN-alpha administration. Of the 163 patients with HCV infection, 30 patients received G-CSF, most of who were maintained on 300 microg of G-CSF once a week. Administration of G-CSF 2 days before or after each dose of PEG-IFN-alpha did not make a significant difference in the neutrophil counts. In the G-CSF arm, 23 of 30 patients (77%) had undetectable end-of-treatment viral response which was comparable with 27 of 30 in the control group (90%; P = 0.17). There was no statistically significant difference in the sustained viral response between the two groups (61%vs 76%, P = 0.18). In most patients PEG-IFN-alpha induced neutropenia improved with a once-a-week dose of G-CSF with a comparable virological outcome. Timing of G-CSF administration did not make any significant impact on the patient's neutrophil counts but was better tolerated when given 2 days apart from PEG-IFN-alpha.

NY State Gudielines for Hep. C. -  http://www.health.state.ny.us/diseases/communicable/hepatitis/guidelines/appena.htm

Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004 Apr;39(4):1147-71. [213 references]

http://www.pbm.va.gov/criteria/GSCFCriteriaForUseforHepatitisC.pdf

Koirala J, Gandotra SD, Rao S, Sangwan G, Mushtaq A, Htwe TH, Adamski A, Blessman D, Khardori NM. Granulocyte colony-stimulating factor dosing in pegylated interferon alpha-induced neutropenia and its impact on outcome of anti-HCV therapy.
J Viral Hepat. 2007 Nov;14(11):782-7.

Revlimid and thalidomide for prostate cancer

Not much is known about the effects of thalidomide and Rvlimid on prostate cancer. At the International Conference on Molecular Targets and Cancer Therapeutics in November of 2005, held in

Philadelphia

,

Pennsylvania

, an abstract was presented by Dr. Robert J. Amato.  This conference was organized jointly by the American Association for Cancer Research, the National Cancer Institute, and the European Organization for Research and Treatment of Cancer.  In Dr. Amato’s paper, eighteen prostate cancer patients were treated with Leukine and thalidomide.  All had rising PSAs following local therapy, and had not previously been treated with hormone blockade.  All of the men in his study had at least a 26% reduction in their level of PSA, with a median reduction of 59%.  His response rate was 100%.

Not much more own about Revlimid, a thalidomide analogue, an oral antiangiogensis inhibitor (it blocks blood vessel growth) that the FDA has approved to treat another cancer called multiple myeloma. Revlimid is closely related to Thalidomide, which has known activity in prostate cancer. In many cases, however, the intolerable side effects of Thalidomide (constipation, fatigue and nerve damage) have precluded its widespread use. Revlimid appears to be much better tolerated, and in a small study by the Cleveland Clinic, it appears to be active when used in combination with Leukine. Sixteen patients were treated with a large dose: 25 mg a day. Nine of the men had some degree of PSA decline. Side effects included low blood counts, diarrhea and fatigue. More studies are awaited.

NCT00348595 is Study of 2 Different Doses of Revlimid in Biochemically Relapse Prostate Cancer

The primary objectives of the study are:

• To evaluate feasibility, safety and tolerance of 6 months administration of Revlimid at 5mg/day and 25mg/day, given orally in subjects with prostate cancer with evidence of biochemical relapse (M0) following local treatment (i.e., surgery or radiation).
• To assess the rate of PSA progression at 6 months after treatment with 5mg/day and 25mg/day of Revlimid (CC-5013) in patients with evidence of biochemical relapse after local therapy

Revlimid is investigational for prostate cancer at this time.

J. A. Garcia, P. Triozzi, S. Smith, B. I. Rini, T. Gilligan, D. Peereboom, P. Elson, E. Klein, R. Dreicer Abstract Phase I/II study of lenalidomide and GM-CSF in hormone refractory prostate cancer (HRPC). No: 229 2007 Prostate Cancer Symposium 

The phase 2 study can be seen here- http://www.druglib.com/trial/95/NCT00348595.html

Decitabine and epigenetic therapy for solid cancers

Lay search: Decitabine is being studies for :epigenetic" therapy of solid cacners.

Genes involved in all aspects of tumor development and growth can become aberrantly methylated in tumor cells, including genes involved in apoptosis and cell cycle regulation. Decitabine, 2´-deoxy-5-azacytidine, can inhibit DNA methyltransferases and reverse epigenetic silencing of aberrantly methylated genes. Nucleoside DNA methyltransferase inhibitors, such as decitabine, have been reported to have antitumor activity, especially against hematologic malignancies. Such demethylating agents have been proposed to reactivate tumor suppressor genes aberrantly methylated in tumor cells, leading to inhibition of tumor growth.

Currenlty Decitabine is FDA approved for myedlodysplaisa. Because of the aforementioned emchanism of action, there is interest in studying it in colorectal and oterh solid cancers. Decitabine has been studied in several phase II trials for solid tumours as well as in different types of leukaemia. The drug has been shown to have very limited efficacy against solid tumours. However, decitabine exhibits higher activity for the treatment of haematological malignancies.

Robert Brown, Jane A Plumb Demethylation of DNA by decitabine in cancer chemotherapyExpert Review of Anticancer Therapy August 2004, Vol. 4, No. 4, Pages 501-510

Saba H, Rosenfeld C, Issa JP, et al. First Report of the Phase III North American Trial of Decitabine in Advanced Myelodysplastic Syndrome. American Society of Hematology Meeting. San Diego, Calif. 2004. Abstract #64.

Kantarjian H, O'Brien S, Giles F, et al.Decitabine Low-Dose Schedule (100 mg/m2/Course) in Myelodysplastic Syndrome (MDS). Comparison of 3 Different Dose Schedules.American Society of Hematology Meeting. Atlanta, Georgia. 2005. Abstract #2522.

http://jco.ascopubs.org/cgi/reprint/JCO.2004.01.947v1.pdf

Adis Decitabine: 2'-Deoxy-5-azacytidine, Aza dC, DAC, Dezocitidine, NSC 127716. R&D Profile Drugs in R & D. 4(6):352-358, 2003.

Jean-Pierre J. Issa DNA Methylation as a Therapeutic Target in Cancer Clinical Cancer Research 13, 1634-1637, March 15, 2007.

Rituximab in treating acquired Factor inhibitors

Acquired factor inhibitors are a significant probelm in patieints with hemophilia and other conditions. All patients who develop an inhibitor should be considered for immune tolerance induction (ITI). The decision to attempt ITI for FIX inhibitors must be carefully weighed against the relatively high risk of reactions and the nephrotic syndrome and the relatively low response rate observed in this group. The start of ITI should be deferred until the inhibitor has declined below 10 Bethesda Units/ml, where possible. ITI should continue, even in resistant patients, where it is well tolerated and so long as there is a convincing downward trend in the inhibitor titre. The choice of treatment for bleeding in inhibitor patients is dictated by the severity of the bleed, the current inhibitor titre, the previous anamnestic response to FVIII/IX, the previous clinical response and the side-effect profile of the agents available. We have reviewed novel dose-regimens and modes of administration of FEIBA (factor VIII inhibitor bypassing activity) and recombinant activated FVII (rVIIa) and the extent to which these agents may be used for prophylaxis and surgery. Bleeding in acquired haemophilia is usually treated with FEIBA or rVIIa. Immunosuppressive therapy should be initiated at the time of diagnosis with Prednisolone 1 mg/kg/d ± cyclophosphamide. In the absence of a response to these agents within 6 weeks, second-line therapy with Rituximab, Ciclosporin A, or other multiple-modality regimens may be considered.

http://www.blackwell-synergy.com/doi/pdf/10.1111/j.1365-2516.2005.01170.x

Wenche Jy et al, Life-Threatening Bleeding from Refractory Acquired FVIII Inhibitor Successfully Treated with Rituximab Acta haematol Vol. 109, No. 4, 2003   

Hay CRM, Baglin TP, Collins PW, Hill FGH, Keeling DM: The diagnosis and management of factor VIII and factor IX inhibitors: A guideline from the UK haemophilia center Doctors' organization (UKHCDO). Br J Haematol 2000;111:78-90

Gleevec for glioblastoma and astrocytoma

Lay Summary: Gleevec is not active in glioblastoma but may have promise in combination with other drugs.

Despite optimal treatment, the prognosis of patients with malignant gliomas remains poor. Patients with glioblastoma multiforme have a median survival of 9 to 14 months, whereas those with anaplastic astrocytomas have a median survival of 24 to 36 months. Once patients develop tumor progression, conventional chemotherapy is generally ineffective, with a median time to tumor progression of 9 to 13 weeks. There is a need for more effective therapies.
Tyrosine kinases play a fundamental role in signal transduction, and deregulated activity of these enzymes has been observed in an increasing number of cancers. There is growing evidence that specific inhibitors of these tyrosine kinases have potential therapeutic applications in oncology and Gleevec is being actively investigated in this disease.  in one phase II component, the 6M-PFS for glioblastoma multiforme patients was 3%, whereas that for anaplastic glioma was 10%. In comparison, a retrospective review of negative phase II trials in recurrent malignant gliomas from the M.D. Anderson Cancer Center found a 6M-PFS of 15% for glioblastoma multiforme and 31% for anaplastic glioma (2). The results are especially disappointing for anaplastic gliomas where the relative importance of PDGF raised the possibility of potential benefit from imatinib.

The European Organization for Research and Treatment of Cancer and the North Central Cancer Treatment Group are also conducting phase II studies of imatinib in recurrent gliomas. In the European Organization for Research and Treatment of Cancer study, glioblastoma multiforme and anaplastic glioma patients were initially treated with imatinib at a dose of 300 mg twice daily, increasing after 8 weeks to 400 mg twice daily if no grade II toxicity was observed. Subsequently, the protocol was amended to treat patients initially with 400 mg imatinib twice daily, increasing to 500 mg twice daily if no toxicity was observed after 8 weeks. The majority of these patients were on EIAED, and there was no attempt to adjust the dose according to the type of AED. Preliminary results of the European Organization for Research and Treatment of Cancer phase II study in glioblastoma multiforme patients showed 3 partial response and 5 stable disease over 6 months in 51 patients, with a 6M-PFS of 15.7%. In anaplastic glioma patients, there was only 1 partial response in 36 anaplastic oligodendroglioma/anaplastic oligoastrocytoma patients and 1 partial response in 25 anaplastic astrocytoma patients. These results are consistent and suggest that imatinib has minimal single-agent activity in malignant gliomas.

The next step was studying Gleevec in combiantion with other drugs. As an example of the trend, I will focus on Gleevec and Hyrea data. Researchers from Germany have reported clinical benefit in 57% of patients with refractory glioblastoma multiforme treated with Gleevec (imatinib) and hydroxyurea. The details of this phase II study appeared in the September 2005 issue of Annals of Oncology. The current trial included 30 patients with progressive glioblastoma multiforme refractory to chemotherapy and radiation therapy. The combination of Gleevec and hydroxyurea led to a 20% response rate and a disease stabilization rate of 37%. The median time to disease progression was 10 weeks and the overall survival was 19 weeks. Three patients continue on therapy for 106 or more weeks. The two-year progression-free survival was 16% with 32% of patients surviving at least six months. These authors suggest that this combination shows promise. Clearly much more investigtion needs to be done before this combination can be routinely prescribed.

Dresemann G. Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Annals of Oncology. 2005;16:1702-1708.
McLaughlin ME, Robson CD, Kieran MW, et al. Marked regression of metastatic pilocytic astrocytoma during treatment with imatinib mesylate (ST0571), Gleevec: a case report and laboratory investigation. Journal of Pediatric Hematology and Oncology . 25:644-648.
Patrick Y. Wen et al, Phase I/II Study of Imatinib Mesylate for Recurrent Malignant Gliomas: North American Brain Tumor Consortium Study 99-08 Clinical Cancer Research Vol. 12, 4899-4907, August 15, 2006
. M.P. Omuro, S. Faivre, and E. Raymond
Lessons learned in the development of targeted therapy for malignant gliomas
Mol. Cancer Ther., July 1, 2007; 6(7): 1909 - 1919.

BCR/ABL monitoring of chronic myelogenous leukemia on Gleevec

There  have been no studies that  demonstrate that followup with BCR/ABL assists with actual clinical management of CML. Chronic myeloid leukemia has become a paradigm for the discovery of target therapeutic approaches in the field of onco-hematology. Recognition of the tyrosine kinase activity of the p210Bcr-Abl oncoprotein led to the development of compounds targeting against BCR-ABL and then controlling the leukemic proliferation. Imatinib mesylate, one of the first tyrosine kinase inhibitors developed, was found effective and safe. According to five-years experience with this drug, it is recommended that the golden standard for initial treatment of newly diagnosis chronic myeloid leukemia patients should be 400 mg Imatinib daily.

It is not clear what the best monitoring stategy of imatinib might be. Some physicians get regular bcr/abl analysis, others only use it for monitoring when Ph chromosome is undetectable. As noted, there is no clear consensus on how to use this test. NCCN does recommedn BCR/ABL every three months.

Gluckman, J. Reiffers, et al.
Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years
Blood, January 1, 2007; 109(1): 58 - 60.

J. V. Melo, T. P. Hughes, and J. F. Apperley
Chronic Myeloid Leukemia
Hematology, January 1, 2003; 2003(1): 132 - 152.

Hematology Disease Site Group. Walker I, Makarski J, Stevens A, Meyer RM. Treatment of chronic myeloid leukemia with imatinib. Toronto (ON): Cancer Care Ontario (CCO); 2004 Jul 16. 27 p. (Practice guideline report; no. 6-15). [39 references]

http://www.cdhb.govt.nz/chlabs/miscdocuments/CML_Monitoring_Guidelines_Jul%202007.pdf