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Newsletter ISH IAD

01/01/2007

Collaborators:

Dr. Guillermo Ruiz Argüelles, Dr. Fernando Cabanillas, Dr. Eileen Pacheco, Dr. Candido Rivera, Dr. Genoveva Martínez Poventud, Dr. Rafael Betancourt, Dr. Pedro Juan Santiago Borrero, Dr. Michael Maldonado and Dr. Norman Maldonado.

Th e Interamerican Division of the International Society of Hematology is continuing the annual Newsletter in order to communicate the latest developments in our fi eld. We will be summarizing the highlights of the American Society of Hematology (ASH) meetings as well as our own International Society of Hematology (ISH) meeting.

We thank our collaborators in this eff ort. Th is newsletter features the highlights of the ASH 2006 meeting in Orlando, Florida, held from December 8 to 12, 2006. Our next ISH congress will be held in Punta del Este, Uruguay, March 21-24, 2007. Information is available at http://www.2007ish.org.

International Outreach:

The American Society of Hematology has an International Program that provides educational material to organizations in developing countries. The material includes online access to Blood, the offi cial journal of ASH, a CD-ROM from the most recent meeting, a copy of Hematology, the Educational Program Book, and a CD-ROM of the visual presentations. Visit the ASH Web site www.hematology.org/education/international for further information.

Advancing acute promyelocytic leukemia (APL) research around the world: American Society of Hematology (ASH) International Consortium:

Since its founding two years ago, the International Consortium on Acute Promyelocytic Leukemia (IC-APL) continues to be a model for collaboration among clinicians. In some developing countries, a lack of infrastructure and funding limits the full potential of cancer research and patient care that can be achieved. Th e IC-APL is working to improve this situation. Th e proper treatment in APL is vital. Among the leukemias, APL is unique in its reaction to all-transretinoic acid. When combined with chemotherapy, this treatment causes long-term complete remissions in 70% to 80% of patients. Th erefore, to improve patient survival, the Consortium designed treatment regimens and patientcare guidelines that are being implemented in several research centers in three developing countries: Brazil, Mexico, and Jordan. Drs. Eduardo REGO, Guillermo J. RUIZ-ARGUELLES, and Mohammed MILHEM act as national coordinators for the program. With the guidance of the ASH International Members Committee, the Consortium brings together researchers from these countries with well-known experts on APL research from the United States, Europe, and Asia via Web conferences and in-person meetings preceding the ASH annual meeting. Funds from North-American, Italian and Mexican institutions have been obtained to support this truly international endeavor.

About a dozen patients with APL from both Mexico and Brazil have been included in the treatment protocol designed by the members of the IC-APL, and the results seem promising. More information about the consortium can be obtained from La- Faundra Neville, ASH Executive Assistant (lneville@hematology.org)

Coagulation Update:

Coagulation issues were among the most important issues presented during the meeting, including the satellite symposia, the educational program, presentations and abstracts.

Bleeding Disorders:

Factor VIII Inhibitors

The role of immunomodulation in the management or Factor VIII inhibitors was extensively presented. Dr. David Lillicrap discussed the subject. Patients with hemophilia can develop inhibitors as alloantibodies following therapy or the novo autoantibodies. The antibody response is quantifi ed using a functional inhibitor assay reported in Bethesda units (BU). Th erapy has been an issue, since there is no specific therapy. If the inhibitor is less than 10, Bethesda unit factor VIII 50 units/ kg three times a week are started, and  ncreased if needed to induce immune tolerance. If the inhibitor is over 10, Bethesda units may need other products, especially concentrates containing the von Willebrand factor and bypassing products. Th e cost is very high. A study presented from Sweden and North Carolina showed that one treatment using an activated prothrombin complex (FEIBA) cost $9,500, and recombinant factor VIIa (Novo Seven) cost $21,300. A novel approach has been reported in some twenty patients who have received anti CD20, rituximab 375 mg/kg weekly for four weeks with good response in 50% to 80% of the patients.

Recombinant factor VIIa (Novo Seven) has become the Holy Grail of hemostasis. Dr W. Keith Hoots discussed the way in which this FDA-approved product provides a bypass to treat patients with hemophilia A and B with inhibitors. Th is causes an increase in thrombin generation in the hemophiliac patient. Th e product has been used in multiple other bleeding scenarios, such as multiple trauma, surgical bleeding and intracerebral hemorrhages. Th ere is evidence of decreased blood loss and also less need for blood transfusions. There has been an increase in thromboembolic complications with its use, both arterial and venous. Myocardial injury has been documented with increases in troponin in 20% of patients, compared with 4% of untreated patients.

In cerebral bleeding, the hematomas decrease in size. It is recommended that blood, plasma, platelet concentrates and cryoprecipitate be given before a closely monitored trial of factorVIIa is used. Two doses of 40 micrograms/kg two hours apart are the suggested doses. Th e cost of this product is very high, and it should be used judiciously.

Acquired factor VIII and other inhibitors are rare and are seen at the rate of one case per million per year. Dr. Alice D. Ma discussed the subject. The mortality rate can vary from 8% to 22%. The inhibitor reaches equilibrium, and some activity is measurable. The condition occurs in older patients, and the bleeding is diff erent than that of hemophilia. One can see mainly purpura, mucosal and soft tissue bleeding and also hematuria. Hemarthrosis are rarely seen. Most cases are idiopathic, but a few are associated with autoimmune diseases. The mixing with normal plasma does not correct the PTT. Factor assays are low and the Bethesda units (BU) help determine the severity.

If less than 5 BU,human factor VIII infusions or DDAVP can be tried. If the titer is >than 5BU, try a bypassing agent as activated prothrombin complex (FEIBA) or high dose of rVIIa (Novo Seven). Plasmapheresis can be tried, but more practical now is rituximab 375 mg/kg weekly for four weeks as an off -label use. Results with rituximab have been rewarding; the inhibitor usually disappears in two weeks. Some are suggesting it should be fi rst-line therapy, since it is less expensive than other products.

Thrombophilia:

Th rombosis and Cancer was presented by Dr. Agnes Y.Y. Lee

There is a close association of thrombosis and cancer in 10% of the patients. Deep vein thrombophebitis (DVT) can antecede cancer, but early detection of the cancer does not necessarily translate into a better prognosis for the patient. Th e procoagulant products interact with platelets, clotting and fi brinolytic proteins to produce DVT. The best characterized cancer procoagulant is the tissue factor, which binds to the activated factor VII. Cytokines such as tumor necrosis factor- á(TNF) and interleukin 1â act on endothelial cells and monocytes. Nitric oxide synthase increases nitric oxide radicals that contribute to thrombogenesis. Th e hypercoagulable state starts with the activation of the clotting cascade and platelets, enhanced endothelial adhesion, suppression of fi brinolysis and inhibition of the protein C pathway.

The tumors most frequently associated with DVT are pancreas, stomach and ovary. Anticancer agents associated with increase risk of thromboembolism (TE) include asparaginase, bevacizumab, bleomycin, cisplatin, 5-fl uorouracil, mitomycin C, tamoxifen, thalidomide and vinca alkaloids. Th e role of anticoagulants in preventing DVT and TE has been debated and low molecular weight heparin (LMWH) has been the most promising. Several studies have failed to confi rm this theory. Studies are in progress with limited disease rather than metastatic disease.

Management of Hereditary Hypercoagulable Disorders:

This subject was presented by Dr. Paula L. Bockenstedt. Low levels of proteins S and antithrombin III may be due more to a temporary acquired defi ciency than to a congenital disorder. Duration of anticoagulation beyond 6 to 12 months must be individualized.

Transient risk factors include contraceptives, post surgical states or immobilization. One third of patients with unprovoked DVT will recur in 10 years. Patients with unprovoked DVT, some 50%, have an underlying thrombophilic defect. Defi ciencies of factor V Leiden (FVL), protein C, protein S, antithrombin III, hyperhomocisteinemia, and antiphospholipid syndrome have an intermediate to high risk for DVT. Heterozygotes for factor V Leiden or prothombin G20210A have a lower incidence of 1.4. Continuous anticoagulation with Coumadin is eff ective, but carries a risk of serious bleeding, which was included in an FDA warning last October 2006. Age, obesity, heart failure and cancer all increase the risk of DVT.

Elevated D dimmers or thrombosis on repeated Doppler testing predict recurrence. In studies, D dimmer elevation had an 18% probability of recurrence in 2 years. A relationship of hormone replacement therapy (HRT) and FVL was found in some patients. Pregnancy carries a 6-fold risk of thrombosis. Recurrent fetal loss is associated with the antiphospholipid syndrome (APS). Treatment with aspirin (ASA) or LMWH is benefi cial. Presence of FVL or PT G20210A mutations account for 20% and 17% of thrombosis, espectively.

Central venous catheters (CVC) are also associated with thrombosis. Elevated levels of factor VIII also have a relative risk of 1.6. Patients must be individualized.

New Anticoagulants:

Direct thrombin inhibition:

New anticoagulants target a single coagulation factor, which includes direct thrombin inhibitors and factor Xa. Two direct thrombin inhibitors (DTI), argatroban and lepirudin, are approved for heparin-induced thrombocytopenia(HIT). Xymelagatran, a very promising agent, was shown to be very effective in preventing DVT, especially after knee replacement. The EXUL trial showed superiority to warfarin. The THRIVE trial showed the same effi cacy as warfarin and LMWH, and it was superior to placebo in revention of DVT. However, it was found to produce a higher incidence of hepatic injury and three deaths. It has been removed from trials by the FDA.

Dabigatran is an oral direct thrombin inhibitor (DTI) that is being compared to warfarin for the prevention of stroke and atrial fibrillation. It was tried in prevention after total knee replacement with good results.

Factor Xa inhibitors:

Fondaparinux is a factor Xa inhibitor that has been studied in four multicenter studies; EPHESUS, PENTHALON 2000, ENTAMARKS, and PENTHIFRA. In EPHESUS, it was superior to enoxaparin in reducing the risk of DVT from 9.2% to 4.1%. It was equally eff ective in PENTATHLON 6.1% to 8.3%. In PENTHIFRA patients undergoing hip fracture, VTE at day 11 was 8.3% in fondaparinux and 19.21% in the enoxaparin group. In the PENTAMAKS trial with knee replacement, fondaparinux prevented DVT, 12.5% to 27.8%. In a metaanalysis it was superior to enoxaparin in preventing DVT, 6.8% to 13%.

Th e OASIS 5 trial in acute coronary syndromes was also favorable for fondaparinux. Fondaparinux was found eff ective in treating heparin-induced thrombocytopenia (HIT).

Th ere is an interest in developing more oral factor X inhibitors. Rivaraxaban used once or twice daily was equally eff ective as standard therapy in preventing DVT. Apixaban is another factor Xa inhibitor undergoing trials.

New Developments in Lymphoma: Several interesting abstracts on the topic of lymphoma were presented at ASH 2006. New drugs are being explored, particularly but not limited to, biologic agents.

Pralatrexate is a novel folate inhibitor designed to have higher affinity for the reduced folate carrier (RFC-1), and is thus more efficiently internalized. Among 16 evaluable patients with T cell NHL, 10 responded (63%); 9 complete remissions [CR] and 1 partial remission [PR]). In the intent-to-treat population, the ORR was 50%. Curiously, this agent has very little activity in B cell NHL with only 1 PR in 18 patients. A new monoclonal antibody, Ofatumumab, binds to a CD20 epitope which is diff erent from the one to which Rituximab binds.

It appears to bind more tightly to the CD20 epitope and, in addition, binds well to cells that express CD20 weakly, such as small lymphocytic lymphoma/CLL, which could represent a signifi cant advantage over Rituximab.

Aside from new drugs, the PET scan is being increasingly explored as a means of defi ning the quality of the response to treatment as well as for adapting therapy according to the metabolic response. Two examples of the application of PET are illustrated below.

Dr. Craig Moskowitz and his group from Memorial Sloan Kettering Cancer Center presented a “Phase II Trial of Dose-Dense R-CHOP Followed by Risk-Adapted Consolidation with Either ICE or ICE and ASCT in Patients with Advanced Stage DLBCL”:

In this study Moskowitz et al used the PET scan as a tool to adapt or modify their therapy of diff use large B cell lymphoma (LDBCL). Eligible patients were those under 65 and/or with at least one ageadjusted IPI risk factor (elevated LDH, stage III/IV or Karnofsky performance status ≤70%).

After a baseline PET scan, patients underwent treatment with dose-dense R-CHOP, and after four courses of therapy the PET scan was repeated. If the post-treatment PET was still positive, they had a biopsy performed. Those who had a positive biopsy underwent treatment with ICE followed by high-dose chemotherapy with autologous stem cell transplant. Those whose post-treatment PET was positive but whose biopsy was negative, had their hemotherapy modifi ed to ICE X3, followed by observation. Finally, those whose post-treatment PET was negative also had ICE x3 followed by observation. Th e fi ndings from this study can be summarized as follows:

1.        31/86 (36%) patients had a positive post-treatment PETscan. Of these, only four (13%) had a positive biopsy.

2.        Of the four whose biopsy was positive, two have relapsed while 4/27 (15%) whose PET was positive but biopsy was negative have relapsed.

3.        Of the 55 whose post-treatment PET was negative, six (11%) have relapsed, a figure not very diff erent from those whose PET was positive but whose biopsy was negative.

4.        Event-free survival for the whole group was 80%.

5.        Age-adjusted IPI and cell of origin did not have any prognostic impact.

Several interesting observations can be derived from this study. In fi rst place, the event-free survival is higher than expected for a group of patients who had an age-adjusted IPI of at least 1. Th is suggests that their new treatment regimen has changed the natural history of the disease. Their new regimen incorporates upfront high-dose chemotherapy and autologous stem cell transplant for those with a positive post-treatment PET and a positive biopsy after R-CHOP and ICE consolidation for all others, irrespective of their PET results. The IPI and cell of origin were no longer important prognostic variables, and this is consistent with this change in natural history. The posttreatment PET scan can be viewed as a prognostic variable, thus it should not be surprising that this factor has also been eradicated as a prognostic variable. In other words, the preemptive administration of ICE x3 after dose-dense CHOP-R might have decreased the adverse impact of a positive interim PET scan.

However, another possible interpretation is that the definition of a positive PET scan was too liberal and, perhaps, the PET was done too late. The authors defi ned a positive PET as anything more  intense than the background mediastinal blood pool. Perhaps a more strict defi nition, such as a higher SUV, might have been associated with a more predictive value of the PET scan. This brings up the issue of what the quantitative defi nition of a positive PET scan should be and when the post-treatment PET should be repeated. These issues are discussed in the next abstract.

Dr. Fernando Cabanilla presented. (Abstract #2433) “The Very Early Post-Treatment PET/CT Scan Performed One Week After First Chemotherapy Course Compared Against the Standard PET After Th ird Course in Histologically Aggressive Non-Hodgkin Lymphoma (NHL)”:

In this study the authors attempted to determine if PET scans done very early during treatment (i.e. one week after the first chemotherapy) already show signifi cant improvement, and if they correlate well with the PET scan performed after the third course of chemotherapy. Another goal was to defi ne quantitatively (i.e. using SUV) what is a molecular complete response by studying the correlation of various SUV cutoff s with failure-free survival. As can be seen in fi gure 1, there was a very signifi cant drop in the median SUV between the baseline pre-treatment PET scan and the one done one week after the fi rst course of chemotherapy. After the third course SUV dropped further.

Various SUV cutoff s were studied for their correlation with failurefree survival, but the one found to correlate best was 5.0, as shown below. The correlation with failure-free survival of the week #1 course #1 PET was better than the course #3 PET. Th e conclusions were as follows:

1.        Striking improvements in PET are seen as early as one week after chemotherapy.

2.        An SUVmax <5.0 on the W1 PET is associated with a significantly superior FFS. Th us, an SUV cut-off of <5.0 at W1 PET can be used to defi ne mCR, and should be prospectively tested in an independent cohort of patients.

3.        Week 1 course PET appears superior to C3 PET in its correlation with FFS.

Update on Chronic Myeloid Leukemia from ASH 2006: The IRIS trial experience of patients receiving imatinib for Chronic Myeloid Leukemia was presented after a fi ve-year follow-up, and published in the NEJM (Volume 355:2408-2417, December 7, 2006)

After median follow-up of 60 months. Kaplan-Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69% by 12 months and 87% by 60 months. An estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial therapy was 89% at 60 months. Patients who had a complete cytogenetic response, or in whom levels of BCR-ABL transcripts had fallen by at least 3 log, had signifi cantly lower risks of disease progression than did patients without a complete cytogenetic response (P<0.001). Grade 3 or 4 adverse events diminished over time, and there was no clinically signifi cant change in the profi le of adverse events. Notably, the rate of disease progression in patients treated with imatinib is apparently trending downward over time.

Strong emphasis was made on testing peripheral blood for bcr/abl by RT-PCR periodically (e.g. q. three months) as the preferred mode of monitoring these patients, obviating the need for repeated bone marrows on patients maintaining a hematologic response. Complete cytogenetic responses / molecular responses can take up to two years from the time of initiating treatment, and consideration should be given to raising the dose of imatinib from the starting dose of 400 mg p.o.daily up to 800 mg p.o. daily, particularly for those patients not achieving complete responses early on. Imatinib-induced cardiomyopathy appears to be a very rare phenomenon, and occurred mostly in patients with baseline cardiac problems. Further studies are indicated.

Second-generation tyrosine kinase inhibitors dasatinib (now FDA approved) and nilotinib appear highly eff ective and safe in  rescuing most CML patients who developed resistance to imatinib (except those harboring the T315I mutation). Clinical trials are now ongoing in which patients who do not achieve a molecular response to imatinib early on can be switched to a second-generation tyrosine kinase inhibitor.

Acute Myelogenous Leukemia: De novo AML patients under the age of 60 are cured with the current treatments in 30% of instances. The most important factors in selecting therapy are the cytogenetic and molecular genetics of each leukemia .The favorable AML include t(15;17)(q22;q12) with a 70-90% cure rate, inv(16)(p13;q22) with a 60% cure rate and t(8;21)(q22;q22) with a 55% cure rate. Th e intermediate prognosis group consists of the normal karyotype and t(9; 11) (p22; q23) each, with a 40% cure rate and the unfavorable prognostic one with complex cytogenetics with less than 5% cure rate. Therapies are now being developed that target the genetic defect, the best example being Acute Promyelocytic Leukemia APL) where therapies have increased the cure rate to about 60-90%.

In t(8;21) and inv (16) leukemia, a very important aspect of molecular genetics has been the discovery of the Core Binding Factor (CBF) in about 13% of patients. Th e CBF is associated with an increase in cure rate from 10-25% to 50-60% with the use of high dose cytarabine (HiDAC). Inv (16) has a better prognosis than t(8;21). Still, 40% to50% of patients younger than 60 years of age are not cured. New approaches are needed to identify these patients, and molecular markers can be of help .For example, the Kit gene is a candidate prognostic marker and the Kit protein, a therapeutic target. Dr. Clara Bloomfi eld reported mutations in the Kit exons 8 and 17; with a frequency of 22% in the t(8;21) and 30% in the inv (16) leukemia, showing that the Kit mutation in exon 17 independently predicted a high relapse rate in patients with these leukemias. This fi nding can have potential therapeutic implications; patients with Kit mutation probably need a more aggressive treatment such as stem cell transplantation (SCT) and perhaps the incorporation of tyrosine kinase inhibitors targeting Kit into current treatment protocols .This is an example of a molecular marker showing independent prognostic significance. Many markers have been shown to have prognostic signifi cance. A large study is required to determine the relation of the various markers and to develop a more useful prognostic and therapeutic classification scheme.

FLT3 Mutations in AML: FLT3 is a single transmembrane receptor with an intracellular tyrosine kinase domain. It belongs to the type III receptor kinase family (KIT, FMS, 2DPGF-Rs), and the FLT3 ligand (FL) stimulates proliferation of hematopoietic/stem and dendritic cells. It is expressed at high levels in over 90% of the blasts population in AML. In 15 to 34% patients with AML, PCR amplification of FLT3 demonstrate internal tandem duplication (ITD) mutations, with the higher rate in older adults. Patients with FLT3/ITD have very poor prognoses, but those with a low allelic ratio of ITD to wild type do not, as this low ratio is a refl ection of a late hit where the mutation occurs in a subclone of the leukemia cells.

FLT3 seats in the membrane of the cell as a single transmembrane receptor, but when it binds to the FL it becomes dimerized, and transphosphorilation occurs. Activated FLT3 then activates multiple pathways (PI-3kinase/AKT, RAS/MAPK and STATS5) that result in blocking of apoptosis and diff erentiation and activation of proliferation.

FLT3 inhibition induces cytotoxicity in the AML with FLT3/ITD mutations. Over thirty drugs that inhibit the FLT3 phosphorilation are being studied. Until now there has been a response in 30% to 50% of patients, but most of them undergoing studies are transitory, lasting weeks to months. Also, an antibody against FLT3 is under study in mice, where a good response has been obtained.

Acute Promyelocytic Leukemia (APL): Th e PML/RARa translocation is essential in the diagnosis of APL, as it is unique to this leukemia. It strongly correlates with the pathogenesis targeted by specifi c therapies, and its detection predicts response to ATRA and ATO. Retinoids act through nuclear receptors (RAR, RXR), which are ligand-inducible transcription factors. Th e retinoid acid receptors recruit a transcription repressor complex with histone deacetylase activity (HDAC). Normally, endogenous ATRA releases the repressor complex and recruits transcription activator. In APL, the PML/RARa heterodimers bind more tightly the repressor complex. Pharmacological doses of ATRA are needed to release the complex and reactivate transcription. Arsenic acid (ATD), on the other hand, induces PML/ RARa degradation with diff erentiation of the cells, and also increases production of reactive oxygen species with the induction of caspases, promoting apoptosis.

Diagnostic confi rmation of the genetic changes is mandatory. Fish allows rapid genetic diagnosis, but does not defi ne the type of PML/RARa. RT-PCR is needed for the baseline characterization of the breakpoint; bcr1- (long transcript) is the most frequent one; bcr3 (short transcript) is found in 40% of the cases, and the bcr2 in 10% to 28% of the cases. Th ese will be the markers for the molecular monitoring in the follow up of the patients. Molecular remission is the goal in the treatment of APL. It should be performed (RT-PCR) at the end of consolidation as an early surrogate of improved survival. Clinicians should refrain from making therapeutic changes on the basis of molecular tests at the end of induction. Treatment in APL consists of three phases. Induction with ATRA and anthracycline-based chemotherapy (simultaneously); consolidation with ATRA and anthracycline-based chemotherapy (2-3 cycles) and maintenance with ATRA and low dose (LD/Chemo). Ara-C should be added to the induction therapy in those patients with high risk APL with WBC over 10,000/mm3 at diagnosis. Clinical studies have not established proven benefi ts for the use of heparin or antifibrinolytic agents to reduce induction death rates in APL. The latter could, when combined with ATRA, potentially increased the risk of thrombotic complications. Leukapheresis for the treatment of hyperleukocytosis is not recommended. Th ere is no role for SCT as frontline therapy. Patients with confi rmed molecular persistence should be considered for salvage therapy including allo-SCT.

THE MYELOPROLIFERATIVE DISORDERS (MPD) IN THE JAK2V617F ERA: This year the American Society of Hematology (ASH) convention emphasized the great and most recent discovery in the MPDs, the JAK2V617F mutation. Th is new finding represents a great advance in hematology, compared to the discovery of BCR-ABL kinase inhibitor therapy for CML. Th ese two modern discoveries are bringing answers to years of questioning and studying.

JAK2V617F represents a guanine to thiamine somatic mutation of JAK2 gene, at nucleotide 1849, in exon 14, resulting in the  substitution of valine to phenylalanine at codon 617 within the pseudokinase domain (JH2). Th is mutation has been detected in approximately 90% to 95% of patients with polycythemia vera (PV), 50% to 70% of patients with essential thrombocythemia (ET), and 40% to 50% of patients with myelofi brosis (MF).

To date, JAK2V617F has not been described in patients with reactive myeloproliferation, lymphoid disorders, or solid tumor. It arises in the hematopoietic stem cell compartment. JAK2V617F is a constitutively active tyrosine kinase that is able to activate JAK-STAT signaling when co-expressed with erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte colony-stimulating factor receptor (GCSFR). Activation of JAK-STAT signaling by JAK2V617F in some, but not all MPD patients with ET and MF led to the identifi cation of the constitutively active MPLW515L allele in ET and MF. Accordingly, there is now molecular justifi cation for grouping PV, ET, and MF together in a distinct MPD category: classic, BCR-ABL- MPD).

Th e discovery of JAK2V617F has already had a major impact on the diagnostic approach to MPDs as well as research strategies, this in terms of both molecular pathogenesis and drug development. Despite these advances, many questions remain regarding the role of a single disease allele in three phenotypically distinct MPD, the potential clinical effi cacy of JAK2 inhibitors, and the identity of oncogenic alleles in JAK2V617F/MPLW515-negative MPD.

The Ubiquitin-Proteasome System in Health and Disease: The ubiquitin-proteasome system was presented in the Wasserman Lecture. A summary of this topic was done by Dr. Jingsong Wang and Dr. Michael Maldonado for this Newsletter.

The ubiquitin-proteasome system is the major pathway of nonlysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, division, apoptosis and modulation of the immune and infl ammatory responses. Th e central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Multiple diseases can arise from the aberration of this system leading to the dysregulation of cellular homeostasis.

Proteasome inhibitors have become novel therapeutic agents in a variety of disease areas, including oncology. Th ey function by entering cells and blocking protein degradation by the ubiquitin-proteasome pathway. Preclinical studies have demonstrated that bortezomib, a dipeptidyl boronic acid, which is a selective and potent inhibitor of the 26S proteasome, decreases proliferation, induces apoptosis, enhances the activity of chemotherapy and radiation, and reverses chemoresistance in a variety of hematologic and solid tumor models.

It has been shown that bortezomib inhibits PKR-like endoplasmic reticulum kinase (PERK), and sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis. Bortezomib have is also capable of inhibiting IêB degradation leading to inactivation of the pivotal pro-survival transcription factor, NF-êB. Bortezomib was the fi rst proteasome inhibitor to enter clinical trials. Recently, bortezomib received FDA approval for the use of multiple myeloma. It is been evaluated for the treatment of mantle cell lymphoma and solid tumors such as thyroid carcinoma among other conditions.

Novel agents for the treatment of multiple myeloma: Th alidomide, Lenalidomide (Revlimid), and Bortezomib (Velcade) are the new hope for patients with this condition. Although these drugs are showing a great improvement in the fight against multiple myeloma, the best treatment is still stem cell transplantation (SCT). Th e Melphalan and Prednisone (MP) regimen was for many years the standard of care for initial therapy in patients who did not qualify for SCT. But now there has been a trend to incorporate new drugs into front-line therapy. These new agents belong to the families of imunomodulatory drugs, and proteasome inhibitors that are active in the relapsed/refractory setting. Th alidomide has been added to the initial therapy for patients between 65 to 70 years old after a study which showed that this was superior to autologous transplant in this age group. Several phase II studies presented revealed that the incorporation of Th alidomide, Lenalidomide, or Bortezomib to MP increased the overall and complete response (CR) rates.

Randomized phase III studies of MP with thalidomide have already shown that, compared to MP alone, the three-drug regimen (MPT, R-MP, & VMP) prolonged time to progression (TTP) and overall survival (OS) in this population, thereby defi ning a new standard of care. Currently there are ongoing studies evaluating V-MPT (fourdrug regimen) after fi rst relapse, with a response rate of 57%. The benefi ts of thalidomide as maintenance therapy are not well established in those with CR and very good partial response (VGPR).

Novel therapies are still associated with CR rates that are less than 40%, since high-dose Melphalan with autologous stem cell transplant is associated with CR rates of over 40%. SCT augments CR rate, progression-free survival (PFS), and overall survival (OS), and MP + the novel agents improve CR rate, PFS, and OS for non-transplant patients.

It is important to remember that until those new antimyeloma therapies can consistently achieve CR rates of 40% or greater, highdose melphalan and SCT remains the standard of care.

Chronic Lymphocytic Leukemia: CLL is the most common leukemia in the US. Stages 0 or I/II without massive adenopathy, splenomegaly, elevated B2 microglobulin or more than 12-month doubling time can be observed. Patients with aggressive disease stages II/III with one of more adverse factors may need therapy. New prognostic factors have been identifi ed that in the future might help determine when earlier or more aggressive therapy is needed. Th ese new parameters include the mutational status of the immunoglobulin heavy chain variable region (IgVH), CD 38 expression on leukemic lymphocyte and ZAP-70 expression.

Elevated soluble CD23 is a bad prognostic factor associated with rapid doubling time. Elevated B2 microglobulin (especially > twice the top normal limit) heralds poor response to chemoimmunotherapy. Th ymidine kinase levels predict disease progression. High levels of CD 38 and ZAP-70 are seen in aggressive disease and unmutated IgVH are also seen in advanced, progressive disease.

Cytogenetic abnormalities by FISH identify risk groups. The 13q - are low risk, the 6q - are intermediate and show plasmacytoid features. The 12 q trisomies are high risk and show atypical morphology and respond to fl udarabine. Th e 11q- is high risk with massive adenopathy, early relapse after ASCT and lower response to fl udarabine.

Th e 17p deletion is associated with loss of p53, the gene coding for the protein p53. Th ose with p53 deletion do not respond to Fludarabine therapy and have a poor prognosis, which can be overcome with the use of Alemtuzumab. Th e goal in CLL is to achieve the eradication of minimal residual disease in order to slow the disease progression and to improve survival.

Th e fl udarabine, cyclophosphamide and rituximab regime has the highest response rate with ORR of 95%. Th e use of Pentostatin has been promising. Alemtuzumab (anti CD52) is approved for the del17p patients, and has improved the CR from 20% to 83% in diff erent clinical trials for residual disease after purine analogue-base therapy. Some patients can benefi t from ASCT.

Novel agents include Flavopiridol, using a new treatment schedule which inhibits CDK with a RR of 50%, Lenalidomide with a RR of 47%, Oblimersen a bcl-2 directed antisense in a phase III trial, Lumiliximab an anti CD23 with a 52% response with the FCR regime, Ofatumumab (CD20 epitope)with a RR of 46% and a chimeric anti CD54 vaccine.

CLL therapy continues to be a challenge, but we learn more about the disease every day.

Myelodysplastic Syndrome: Th ere has been progress in the treatment of myelodysplastic anemia. Ledolinomide has been approved for the 5q- patients with 67% transfusion independence. Some patients increase an average of 5.4gm/dl., and there is a 45% cytogenetic response. Th ere are side effects, most notably drops in WBC and platelets of close to 55%. Twice weekly CBC should be done initially. Dr James Vardeman discussed the subject of myelodysplasias, dysplasias, hypoplastic myelodysplasias, atypical myeloproliferative syndromes, macrocytosis of the elderly and secondary macrocytosis due to hypothyroidism, alcoholism, chronic liver disease and antiepileptic and other drugs.

Dr Schiffer discussed the new drugs such as azacytidine with a 21% CR and PR response. Dacitibine has a 17% response. In the hypoplastic group ATG can be used with a 48.5% response in selected patients. Ledalidomine has a 25% response in heavily transfused non 5q- patients.

Erythropoietin has an initial role in patients with EPO levels below 500. GCSF can add to the EPO response. New chelation agents such as deferasirox (Exjade) can help with the heavily transfused patient with iron overload. The problem is that all the treatments are very expensive, and many of them may not be covered by health plans. However, the companies have compassionate programs for the medically indigent.

Th rombosis in infants and children: Th is conference was presented by Dr Reinhard Schneppenheim and Dr. Jeanette Greiner. They reported that during the past ten years thromboembolism (TE) has become increasingly recognized as a disorder with a signifi cant impact in morbidity, mortality and development of children in most countries of the world. Th e annual incidence is considerably lower than in adults. Pain, swelling and discoloration of the extremities are common acute symptoms of deep vein thrombosis (DVT). Inferior vena cava thrombosis manifests with prominent cutaneous veins. Superior vena cava thrombosis leads to cyanosis and swelling of the head and upper thorax. Portal vein thrombosisis is due to central venous catheters.

Acute chest pain in patients with risk factors favors venous TE and pulmonary emboli (PE). Headaches, visual disturbances, seizures and venous congestion may indicate cerebral venous sinus  thrombosis. Central venous catheter-associated thrombosis show loss of patency. An arterial ischemic stroke in neonates shows with seizures and poor muscle tone, while in older children shows with hemiparesis. Congenital or acquired protein C or S defi ciency may present with purpura fulminans, retinal occlusion and necrosis of distal limbs. Laboratory shows increases in D-dimers and Factor VIII levels in 67% of pediatric patients. Imaging with color Doppler ultrasound, echocardiography and angiographic MRI is useful.

Th e hereditary thrombophilias include heterocygocity for prothrombin 20210A mutation, Factor V Leiden, elevated factor VIII (with unfavorable prognosis), antithrombin III, defi ciencies of protein C and S and the VWF-cleaving protease ADAMTS 13. Th e latter can cause TTP, and can be caused by acquired antibodies against ADAMTS 13. Central venous catheters and systemic infections can cause DVT.

Cancers, including acute lymphatic leukemia, are associated with TE. Antiphospholipid syndrome, and heparin-induced  thrombocytopenia (HIT) can be seen. Th e therapy with heparin for 5 to14 days is the best. Low molecular weight heparin (LMWH) is used most often. Thrombolytic agents (r-tPA) should be used rarely by experienced personnel. Vitamin K antagonists are rarely used.

PROMINENT DRUGS IN 2006:

Rituximab (RITUXAN):

A total of 859 abstracts mentioned rituximab. New uses of rituximab for immunologic disorders includes ITP, AIHA, cold agglutinin disease and coagulation inhibitors in hemophilia and in acquired inhibitors.

Recombinabt factor VIIa (Novo Seven):

It has become the Holy Grail of hemostasis. It is approved for acquired inhibitors in hemophilia A and B and, now, factor VII defi ciency. It is widely used in cardiac surgery, multiple trauma bleeding, orthopedic surgery and postpartum bleeding. Has risk of thrombosis. Benefi ts 70% and can have complications in 6% of patients in some studies.

Needs to be used with caution at lowest doses initially. It is expensive.

Bortezomid (Velcade):

Th e use in multiple myeloma has been promising, and it is moving up to front line therapy. Now is in use in mantle cell lymphoma, other lymphomas, and solid tumors, including thyroid carcinoma. It promises to be a great drug, as the fi rst proteosome inhibitor to be used clinically.

Dasatinib (Sprycel):

Th is new drug for patients with chronic myelogenous leukemia who fail imatinib, promises to be of value to extend disease-free survival and overall survival in these patients. Other uses are undergoing clinical trials.

Fondaparinux (Aristra):

Th is new anticoagulant is an inhibitor of factor Xa that has shown promise as an anticoagulant to prevent DVT in post-operative patients in orthopedics, general abdominal and gynecologic surgery. It has been shown in a large Canadian trial to be eff ective in patients with ischemic myocardial events, compared with enoxaparin. Both reduced myocardial infarction or death to 5%. Bleeding was less with fondaparinux, 2% vs. 4%. It may replace other prophylactic heparins in the near future.

Lenolidomide (Revlimid):

Is has been approved for the treatment of transfusion-dependant myelodysplastic anemia with the 5q deletion. It has also showed excellent response in multiple myeloma, even as frontline therapy with dexamethasone. It can produce neutropenia, thrombocytopenia, DVT and pulmonary emboli.

 

“Triple-S congratulates the International Society of Hematology in the XXX1st World Congress to be held in Punta del Este Uruguay.”

March 20-24, 2007

Triple-S Company Profile

Triple-S, Inc., the leader in the Puerto Rico’s health insurance industry, serves more than a million people throughout the island with vast experience and a wide array of resources. Th e company also provides service programs such as Teleconsulta, a health assistance telephone line that operates 24 hours a day, 7 days a week, and Teleconsejo, a professional and confidential counseling line for any concern patients may have in their everyday lives.

Triple-S has an extensive network of healthcare providers in Puerto Rico, with more than 10,000 doctors, dentists, pharmacies, laboratories and hospitals. Triple-S is an independent licensee of the Blue Cross Blue Shield Association, providing fi rst-class medical care in the US though the Blue Card Program and off ering worldwide coverage through the Blue Card Worldwide Program.

Triple-S, Inc.

Franklin D. Roosevelt Avenue 1441

PO Box 363628, San Juan, P.R. 00936-3628

Tel.(787) 749-4156 Fax. (787) 749-4093

www.segurostriples.com