Cancer Treatment

Thalidomide for Myelodysplasia (MDS)

Thalidomide exerts in vitro heterogeneous biological effects on hematopoiesis which have supported its possible use in treating myelodysplastic syndromes (MDS). Some recent clinical trials have confirmed that thalidomide may improve anemia and, less frequently, other cytopenias, in a proportion of younger patients with low-risk MDS (11–56%, on intention-to-treat analysis). Of interest, erythroid responses may be achieved also in transfusion-dependent subjects with high serum levels of endogenous erythropoietin, a subset of MDS patients with little chance of responding to recombinant erythropoietin, alone or in combination with G-CSF.

Although the FDA currenlty apporvies thalidomide only for the 5q- deletion, there are many trials confirming effectiveness , albeit lesser effectiveness, in patients with MDS who do not have this deletion.NCCN mentions thlidomide and notes that it has greater effectiveness in the cases with 5q- deletion.Thus, it is recognized as a reasonably effective treatment for MDS, even without the 5q- diletion.

P . Musto Thalidomide therapy for myelodysplastic syndromes: current status and future perspectives .  Leukemia Research , Volume 28 , Issue 4 , Pages 325 - 332, 2004

http://www.moffittcancercenter.com/CCJRoot/v11s6/pdf/07.pdf

nccn.org, myelodysplastic

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

Donor lymphocyte infusion to treat chimerism

The donor cell reinfusion in this case is not being used to provide new graft versus leukemia effect but to destroy remaining normal patient cells and to provide engraftment. It ahs been observed that chimerism is risk factor for relapse of the leukemia. The status of DLI to treat disase is still unsettled and the use of DLI to decrease chimerism is even less established. There would have been no objection to a reinfusion of stem cells to re-engraft which I would see as a continuation of the previously approved stem cell transplant. However, using DLI in this fashion is experimental since the contention that it does os is supported by case reports and series only

Because of the large number of acute leukemia patients who relapse after alloBMT, there has been a substantial experience in the treatment of these patients with DLI. Using median doses of >/=108 T cells/kg, DLI alone induces complete remissions in 8% of patients with ALL and 22% of patients with acute myeloid leukemia (AML). When patients who receive chemotherapy prior to DLI are included, complete response rates are significantly higher, ranging from 33% to 37%. However, follow- up of ALL patients reveals few, if any, long-term survivors, although 1 has been reported. Relapse occurs in approximately one quarter to one half of patients with AML in remission after DLI, leaving a long-term survival rate of approximately 10% to 15%.

DLI has been researched as a treatment for a variety of hematologic malignancies, including most prominently chronic myeloid leukemia, but also acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, myelodysplastic syndromes, chronic lymphocytic leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma. Studies are limited due to small numbers but they have provided evidence that DLI can establish a graft-versus-leukemia/lymphoma effect.

Fewer patients with relapsed myelodysplasia have been treated with DLI. However, because myelodysplasia progresses more slowly than AML, the rate of complete remissions may be higher. The natural history of myelodysplasia patients who enter into a remission following DLI has not been described.

It is not clear whether administration of induction chemotherapy at the time of relapse improves long-term survival following DLI. It is usually thought that it does but without a strong conifrmation in the literature. A randomized trial with analysis performed on an intent-to-treat basis is needed to answer this question.

Litzow, Mark R Progress and strategies for patients with relapsed and refractory acute myeloid leukemia. Current Opinion in Hematology. 14(2):130-137, March 2007.

Luznik L, Fuchs EJ. Donor lymphocyte infusions to treat hematologic malignancies in relapse after allogeneic blood or marrow transplantation.Cancer Control. 2002 Mar-Apr;9(2):123-37.

Ishikawa J, Maeda T, Kashiwagi H, et al. Successful second allogeneic peripheral blood stem cell transplantation and donor leukocyte infusion in patients with relapsed acute leukemia using the same donor as for the initial allogeneic bone marrow transplantation. Bone Marrow Transplantation. 2003; 31:1057-1059.

Levine JE, Braun T, Penza SL, et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem cell transplantation. J Clin Oncol. 2002; 20(2):405-412.

E . Orsini , E . Alyea , A . Chillemi , R . Schlossman , S . McLaughlin , C . Canning , R . Soiffer , K . Anderson , J . Ritz Conversion to full donor chimerism following donor lymphocyte infusion is associated with disease response in patients with multiple myeloma . 
Biology of Blood and Marrow Transplantation , Volume 6 , Issue 4 , Pages 375 - 386, 2000

Suradej Hongeng et al, Donor Lymphocyte Infusion Can Eliminate Mixed Chimerism in Nonmyeloablative Stem Cell Transplantation for Correction of Hyper-IgM Syndrome Acta Hematologica Vol. 114, No. 3, 2005

Revlimid for Myelodysplastic syndrome (MDS)

Lay Summary: Revlimid is FDA approved for low risk and 5Q- mutation of MDS 

Lenalidomide, an oral immunomodulatory agent, has received approval in the USA from the Food and Drug Administration (FDA) for the management of myelodysplastic syndromes (MDS) classified by the International Prognostic Scoring System (IPSS) as low risk or intermediate-1 risk and with a deletion 5q (del(5q)) cytogenetic abnormality. Although some patients with del(5q) have a relatively good prognosis, all del(5q) patients will become transfusion-dependent at some point during the course of their disease. The results of two clinical trials in more than 160 patients with MDS have demonstrated clear therapeutic benefits of lenalidomide, with >60% of patients achieving independence from transfusion during therapy, irrespective of age, prior therapy, sex, or disease-risk assessment. The recommendations are for this subset of MDS pateints; in other subgroups responses are around 15-20%.

Revlimid is very teratogenic and has been associated with increased risk of deep vein thrombosis and pulmonary embolism. Patients should receive education on the symptoms associated with these conditions, and seek medical help immediately if symptoms appear. It is unknown if prophylactic anticoagulant therapy is effective in reducing this risk; any such treatment course should be administered under the close supervision of a medical professional.

Giagounidis AA, Germing U, Strupp C, Hildebrandt B, Heinsch M, Aul C. Prognosis of patients with del(5q) MDS and complex karyotype and the possible role of lenalidomide in this patient subgroup Annals of Hematology 2005 Sep;84(9):569-71. Epub 2005 May 13.

Dredge K, Horsfall R, Robinson SP, Zhang LH, Lu L, Tang Y, Shirley MA, Muller G, Schafer P, Stirling D, Dalgleish AG, Bartlett JB. Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro Microvascular Research 2005 Jan;69(1-2):56-63

List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes New England Journal of Medicine 2005 Feb 10;352(6):549-57

Neumega in myelodysplasia

The myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by ineffective hematopoiesis and persistent peripheral cytopenias. These disorders typically are difficult to manage, and the advanced age of most patients renders administration of therapy challenging.THis case as described is difficult as the patient has thromboocuyopenia and having reactions to platelt transfusions.

The survival of patients with MDS is poor, and fatal complications of MDS-associated peripheral blood cytopenias are common. Life-threatening bleeding occurs less frequently than infection in patients with MDS but still represents a major problem. The reported incidence of hemorrhagic complications in the literature ranges from 3% to 53%, and the frequency of hemorrhagic deaths is on the order of 14% to 24%. Both thrombocytopenia and platelet dysfunction may contribute to hemorrhagic complications observed in patients with MDS. Three agents are approved by the US Food and Drug Administration (FDA) for the treatment of MDS -- azacitidine, decitabine, and lenalidomide -- although none is specifically approved for the treatment of thrombocytopenia in MDS. Most of these drugs cause at least transient cytopenias if they are to be effective, making difficult the interpretation of their effect on platelet counts.

Neumega (Oprelvekin), a recombinant human interleukin (IL)-11, stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitors and induces increased platelet production through megakaryocyte maturation.[ It is approved by the FDA for the prevention of severe thrombocytopenia following myelosuppressive chemotherapy in patients with nonmyeloid malignancies at high risk for this toxicity. Two small single-arm studies have explored the use of oprelvekin in patients with bone marrow failure, including those with bone marrow failure due to MDS. In a pilot study, median platelet counts at baseline were 12 x 109/L; 38% of patients showed a platelet response. Of the 6 responders, 1 had refractory anemia (RA), 1 had RA with ringed sideroblasts (RARS), and 3 had RA with excess blasts (RAEB); the remaining responder had aplastic anemia. The duration of platelet response ranged from 12 weeks to > 30 weeks.[35] In the second study, median platelet counts were 17 x 109/L at baseline and 27% of patients responded to treatment, with either a major or minor platelet response (6 patients) or a multilineage response (3 patients).] Of the responders, 4 had RAEB, 1 had RARS, and the remainder had chronic myelomonocytic leukemia or aplastic anemia. The duration of response ranged from 1.4 to ≥ 34.5 months. Most of the toxicities observed in these trials were mild (peripheral edema, conjunctival infection, fatigue, arthralgia, and myalgia). However, 1 patient in the second study had a transient ischemic attack after completing treatment and 1 patient developed atrial fibrillation/supraventricular tachycardia. Other cardiovascular events, such as arrhythmias and pulmonary edema, have also been observed in oprelvekin-treated patients. Oprelvekin also has been associated with allergic and hypersensitivity reactions, including anaphylaxis, and serious fluid retention, which has been fatal in some patients. Papilledema has also been reported and is more common in children; therefore, oprelvekin is not indicated for use in the pediatric population. It is also not indicated for use following myeloablative chemotherapy; a clinical study showed a significant increase in side effects in this population compared with placebo. The evidence for activiry of Neumaega in MDS is preliminary.

Tsimberidou AM, Giles FJ, Khouri I, et al. Low-dose interleukin-11 in patients with bone marrow failure: update of the M. D. Anderson Cancer Center experience. Ann Oncol. 2005;16:139-145. Abstract
Kurzrock R, Cortes J, Thomas DA, Jeha S, Pilat S, Talpaz M. Pilot study of low-dose interleukin-11 in patients with bone marrow failure. J Clin Oncol. 2001;19:4165-4172

Vidaza, Dacogen for Myelodysplasia

Lay Summary: I review some of the new drugs for myelodysplastic syndromes.

The main options available to MDS patients in the past were blood transfusions, antibiotics to prevent infection and blood cell growth factors, drugs designed to jumpstart blood cell production. Today, almost all patients still receive blood transfusions, but transfusions don’t provide long-term relief and repeated red blood cell transfusions often leave patients with iron-rich blood, a serious condition if left uncorrected. (Last year’s approval of Exjade® [deferasirox], the first oral drug designed to reduce iron overload, now makes the consequences of transfusion therapy less intrusive by replacing traditional infusion-based pump therapy.)

Donor stem cell transplant—currently the only curative treatment for MDS—may not be realistic for this older population.

Both Vidaza (5 azacytidine) and Dacogen (decitabine) are DNA methyltransferase inhibitors (DMTI) approved by the FDA for use in all French- American British (FAB) categories for MDS. In its pivotal trial, Vidaza was reported to produce a 60% response rate (RR) (7%CR, 16%PR 37% hematological improvement). Vidaza prolonged median time to progression (TTP) to MDS/acute myeloid leukemia (AML) from 12 months to 21 months (p=0.07). The response rates for Dacogen were 30% (9% CR, 8% PR, 13% HI). Median TTP was prolonged from 7.8 months to 12.1 months compared to supportive care (p=0.1). Higher response rates have been reported in a single institution trial using lower doses of Dacogen.

Silverman L, Demakos E, Peterson B, et L. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J. Clin. Oncol 2002; 10: 2241-2252.

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.

Allogeneic stem cells for Myelodysplasia (MDS)

Lay Summary: Allogeneic  stem cell transpalntation is standard of care for younger patients with MDS.

The guidelines recommend that all patients < 65 years should be assessed for fitness/eligibility for allogeneic SCT as soon as possible after diagnosis, as SCT outcome is improved if performed early. If eligible and a sibling donor is available, it is recommended that patients < 50 years are offered ablative allogeneic SCT (evidence grade B, level IIb) and patients > 50 < 65 years are considered for non-ablative allogeneic SCT, within clinical trials where available (evidence grade C, level IV). Patients with no sibling donor, but with an unrelated donor should also be considered for ablative unrelated-donor SCT (< 40 years, evidence grade B, level III) or non-ablative unrelated-donor SCT within clinical trials (> 40 years, evidence grade C, level IV), though the TRM from these procedures remains high. Intensive cytoreductive chemotherapy prior to SCT is not recommended for this group (evidence grade B, level IIb). Anotehr option is chemotherapy plus SCT. All patients < 65 years should again be considered as to fitness/eligibility for stem cell transplantation early after diagnosis. In this group of high-risk patients, stem cell transplantation should only be considered for those responding to remission induction chemotherapy (complete/good partial response) as the outcome for non-responding patients is very poor (evidence grade B, level IIb). Large cohort studies are available for the assessment of ablative sibling and unrelated allogeneic SCT but the role of autologous and non-ablative SCT is yet to be clearly defined. Nevertheless, TRM is lower for both modalities and preliminary evidence suggests that both will have a future role.

Chemotherapy alone. Both patients > 65 years and those < 65 years who are ineligible for stem cell transplantation should be considered for intensive chemotherapy alone. There have been no prospective randomized, controlled trials evaluating outcome following intensive chemotherapy compared with supportive care alone in MDS. Cohort studies suggest that of all high-risk MDS patients (≥ INT-2), those with RAEB in transformation (RAEB-t, 20–30% marrow blasts) and lacking an independent adverse risk factor [karyotype, age, performance status, length of antecedent haematological disorder (. Thus, intensive chemotherapy alone is recommended for consideration in these patients. No chemotherapy combination is clearly superior, but most commonly used regimens contain cytosine arabinoside with any of an anthracycline, etoposide and/or fludarabine. The median number of chemotherapy courses in most studies is two (one induction and one consolidation) and patients rarely tolerate more than this.

David Bowen, Dominic Culligan, Simon Jowitt, Stephen Kelsey, Ghulam Mufti5, David Oscier6, Jane Parker5 of the UK MDS   Guidelines Group Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes British Journal of Haematology Volume 120 Page 187  - January 2003

Corey Cutler, Joseph H. Antin Peripheral Blood Stem Cells for Allogeneic Transplantation: A Review Stem Cells, Vol. 19, No. 2, 108-117, March 2001