From: bruce
Email: sales@aebiz.com
Date: 6/6/2001
Time: 12:28:38 AM
Remote Name: 24.169.74.83
Date: Wed, 12 Jan 2000 09:55:29 -0700 Reply-To: "Aplastic Anemia and Myelodysplastic Syndrome support list." <AA-MDS-TALK@LISTSERV.AOL.COM> Sender: "Aplastic Anemia and Myelodysplastic Syndrome support list." <AA-MDS-TALK@LISTSERV.AOL.COM> From: "D.West" <chitur18@IMT.NET> Subject: Re: MDS Treatment Report reprint Content-Type: text/plain; charset="iso-8859-1" Hi Listmates: This is for the new listmates, this paper will answer some of their questions.It was sent by Hans Provenier in 1999. +++++++++++++++++++++++++++++ Subject: [AA-MDS] MDS Treatment Report October 1998 > Dear listmates, > > I have re-scanned the entire text part of the Haematologica issue of October > 1998 and formatted to the AOL browser. > Oh yeah, there's a massive list of aknowledgements and referals to colleagues. > > > Recent Advances in Myelodysplastic Syndromes > > Guest Editor: Migel Angel Sanz, Guillermo Sanz & Temsa Vallespf > > A patient-oriented approach to treatment of myelodysplastic syndromes > > MARIO CAZZOLA,' JEANNE E. ANDERSON,' ARNOLD GANSER,L EvA HELLSTROM-LJNDBERG' > > 'Department of Internal Medicine and Medical Therapy, Section of Internal > Medicine and Medical Oncology, Univers of Pavia School of Medicine, IRCCS > Policlinico S. Matteo, Pavia, Italy,, 'Department of Medicine, Division of > Hematology, University of Texas Health Science Center at San Antonio, USA; > 'Department of HematologylOncology, Hannover Univer- > sity Medical School, Hannover, Germany,, *Department of Hematology, Huddinge > University Hospital, Huddinge, Sweden. > > Abstract > > Background and Objective. There are several therapeutic options for patients > with myelodysplastic syndrome (MDS) but most of them are poorly effective and > the potentially curative ones are available only for a minority of > Individuals. The aim of this article Is to define a rational basis for a > patient-oriented approach to treatment of MDS. > > Evidence and Information Sources. All four authors have done clinical studies > of treatment of MDS, Including stem cell transplantation, Intensive and low- > dose chemotherapy, and use of hematopoletic growth factors. They also > participated In the Fourth lntemational Symposium on MDS (Barcelona, 24-27 > April 1997). In addition, the present review critically examines relevant > articles and abstracts published In journals covered by the Science Citation > Index- and Medline-. > > State of the Art and Perspectives. At present, the only two treatments that > can prolong survival are allogoneic stem cell transplantation (SCT) and > Intensive chemotherapy, but only a minority of MDS patients can really benefit > from them. The heterogeneity of MDS patients, the wide variety of patient > Inclusion cri. teria and transplant procedures used, and mkfflvety small > numbers of patients In the Individual reports of allogenoic SCT make It > difficult to draw many definitive conclusions. However, approximately 40% of > patients with MDS who are eligible for allogeneic SCT are likely to be cured > by this treatment. Intensive chemotherapy with a combination of cytosine > arabinoside and an arrthracycline should be offered to all patients with an > Increase In bone marrow blasts who are not ellglble for allogeneic SCT, > especially @ patients up to 65 years of age. Complete remission rates are > similar to the" olaalned In patients with acute myelogenous leukemia, but > probability of long-term survival Is low. The remaining treatments val@ dated > In clinical trials (erythropoietin and/or granulocyte colony stimulating > factor, lo@ cytosine arabinoside) can Improve the efficiency of hematopoiesis > in subsets of patients. Responsive Individuals might experience an improvement > in quality of life but very few studies have addressed this question so far. > The majority of MDS patients still rely upon supportive therapy. A clinical > decision path based on findings of clinical trials and the patient's > expectations can help physicians In decision making. Because of the > Inadequacies of all current treatment modalities, participiation In clinical > trials should always be encouraged. 01998, Forrata Storti Foundation > > Key words: myelodysplastic syndromes, therapy. > > Recent papers in this journal have analyzed the pathogenesis and clinical > features of myelodysplastic syndromes (MDS). For the purpose of this article > on the therapy of MDS, the following two points need to be recollected: > > a) MDS are clonal disorders of hematopoiesis in which peripheral blood > cell production is inefficiently sustained by hematopoietic progenitors > belonging to the abnormal clone(s).' A few observations indicate that the > normal hematopoietic stem cell reservoir may be preserved early after > diagnosis, but undergoes decline with time, so that most patients with long- > lasting, advanced disease would have very few normal residual stem cells left; > b) Although the disease progression is highly variable from patient to > patient, the International Prognostic Scoring System (IPSS) provides an > improved method for evaluating prognosis in individual MDS patients, as long > as they remain untreated. > > The list of therapeutic options available for MDS patients is as long as the > list of names previously used for defining these conditions.' Unfonunately > most of these therapeutic tools are poorly effective, especially when given to > unselected patient populations, while the potentially curative ones (see > later) are available only for a minority ofindividuals. Facing an individual > patient with MDS and bearing the above considerations in mind, as clinicians > we first have to define treatment objectives. We basically have three choices: > > 1 ) to avoid any manipulation of hematopoiesis and just rely upon supportive > therapy; > > 2) to stimulate normal residual hematopoietic progenitors and/or improve > the efficiency of the myelodysplastic hematopoiesis; > > 3) to eradicate the myelodysplastic clone and restore a normal (autologous > or allogeneic) polyclonal hematopoiesis. > > We will first consider the single therapeutic options within each ofthe above > categories and then shall propose a patient-oriented approach to MDS therapy. > > Therapeutic options for MDS patients > > Before making therapeutic decisions we recommend that the diagnostic process > be carefully reviewed in order to be sure that the individual patient has MDS. > This diagnosis is often difficult and diagnostic errors are possible, some > being quite common while others more rare. Among the former must be included > megaloblastic anemia and anemia associated with otherdisorders. With respect > to more subtle misdiagnoses, Coccer et aL' reported a previously unaffected > 77-year-old male who developed severe anemia: the initial diagnosis was > sideroblastic anemia with ring sideroblasts. This patient responded > dramatically to pyridoxine with normalization of hemoglobin values. Since > anemia was microcytic, he was studied for point mutations in the eythroid- > specific delta-aminolevulinate synthase gene (ALAS2) and found to have an A to > C transversion in exon 7. This patient therefore had a late-onset form of X- > linked sideroblastic anemia,'@ which can be distinguished from refractory > anemia with ringed sideroblasts (RARS) by microcycosis, pyridoxine- > responsiveness, and ALAS2 mutations. > > Watchful-walting strategy > > The approach to a patient with MDS should begin with a period ofobsemation, > with sequential peripheral blood counts - and sometimes bone marrow > examinations - to assess the rate of progression, if any. Not all patients > need be treated. A considerable portion ofMDS patients have Hb levels > 9-1 0 > g/dL, neutrophil count > O.5x 10 9/L and platelet count > 5OX 10 9/L In > elderly patients such Hb levels may be compatible with a reasonably good > quality of life, and the above degrees of granulocytopenia and > thrombocytopenia are generally nottroublesome and canjust be followed > regularly. In addition, occasional patients may have spontaneous improvement > in blood counts. > > Responses ofanemia to androgens,"." ofgranulocycopenia to corticosteroids," > and of thrombocytopenia to danazol" have been reported but they do represent > the exception rather than the rule, and anecdotal positive evolution in a few > patients cannot be formally ascribed to a drug. For instance, a careful study > did not support a positive effect of dan@ol in MDS patients during long term > follow-up." Therefore, we do not recommend the regular use ofandrogens and/or > corticosteroids in MDS patiencs. If the clinical condition is stable and a > curative treatment is not feasible, close follow-up with no treatment may be > the best choice. > > > > Table 1 Crtteria for supportive therapy in MDS patients. > > Anemia > Red cell tansfsions should be given when anemia is symptomatic. > Any low or intermediate-1 risk patient (with an average life expectancy > 4 > years according to the IPSS) who has received at least 30 blood transfusions > or how Serum ferritin is >=1,000 pg/L Should be ug.liter should be regularly > treated with subcutaneous desferrioxamine, 30-40 mg/kg daily for 5 days a > weak. > > Granulocytpenia > Since there is no clear evidence that regular administration of G-CSF can > prevent infective episodes and/or prolong survival in neutropenic MDS paben@, > this use is not recommended. Hoever, individual patients may benefit from > short-term treatment ith G-CSF during an infective episode. > > Thrombocytopenia > Platelet transfusions should be given when the platelet count drops below > 10x10 9/L, or with higher platelet counts during hemorragic episodes. > > > > Supportive treatment > > Once a cytopenia becomes symptomatic, supportive therapy with blood products > and conservative measures are still the mainstay oftherapy (Table 1 ). > > Symptomatic anemia requires regular transfusions of red cells, and > transfusions iron overload is inevitable. One unit of blood (400 mL) contains > about 200 mg ofiron, so that the annual burden may be 2-4 g on average. > Although transfusional iron is primarily taken up by the reticuloendothelial > cells, it is later redistributed to parenchymal cells, with the redistribution > rate being proportional to erychroid proliferation and plasma iron turnover. > When the body iron load exceeds 100-200 mg/kg, secondary hemochromatosis > develops and liver disease, diabetes mellitus, hypogonadotropic hypogonadism, > and eventually heart failure may occur. We believe that any low or > intermediate-1 risk patient (with an average life expectancy @ 4 years > according to the IPSS) who has received at least 30 blood transhisions or > whose serum fe"itin is @ 1,000 pg/L should be regularly treated with > subcutaneous desferrioxamine, 30-40 mg/kg daily for 5 days a week. Long-term > desferrioxamine iron chelation therapy has been proven to be effective not > only in retarding but even reversing organ damage caused by transfusional iron > overload." Individuals with poor compliance to a conventional subcutaneous > pump, may benefit from subcutaneous bolus injections (I g twice daily)." > Inmostinstances,this latter posology may represent the most practical way of > desfemioxamine administration. Regular iron chelation therapy with > desferrioxamine may reduce red blood transfusion requirements and improve the > degree ofcytopenia in MDS patients."," However, the mechanism underlying these > effects is unclearand these findings require confirmation in prospective > clinical trials. The use of deferiprone (Ll) as an oral iron chelator must be > considered strictly experimental for several reasons, including the risk of > agranulocytosis. Treatment of infections should follow standard criteria. > There is no clear evidence that the regular use ofgranulocyte colony- > stimulating factor(G-CSF) can prevent infective episodes and/or prolong > survival in neutropenic MDS patients, so that we do not rec- > ommend its routine use. However, individual patients may benefit from a > short-term treatment with G-CSF during an infective episode, particularly in > the case of fungal infections. > > Severe thrombocytopenia can be a major clinical problem in some MDS patients. > A recent study in leukemic patients" has clearly shown thac the risk of major > bleeding during induction chemotherapy is similar with platelet-transfusion > thresholds of 20x 1o 9/L and 1Ox 1O 9/L. Therefore, we recommend using the > lower threshold in MDS patients as well. > > Differentiating agents > > The rationale for differentiation therapy in MDS is to overcome the phenotypic > differentiation arrest and to induce a normalization ofdifferentiation with > normally functioning mature cells. Based on the finding with leukemic cell > lines, clinical trials have been performed with retinoic acids, vitamin D3, > interferons, hematopoietic growth factors, certain chemical dif- > ferentiation inducers, e.g. hexamethylene bisacetamide (HBMA), and > combinations of three.' > > 13-cis-retinoic acid (13-cis-RA) was the first retinoid to be studied in the > treatment of MDS (Table 2). 'Treatment had to be given for prolonged periods. > The response rates were small with no prolongation of survival. Two randomized > trials, have been reported. In the trial by Clark et al. in 98 patients, the > treatment group received 20 mg/ml/day 13-cis-RA while control patients > received only supportive care; in patients with more than 5% blasts in the > marrow, low-dose cycosine arabinoside (ara-C) was initially given, and 13-cis- > RA was added after 12 weeks. Them was no difference in overall survival after > 25 months, except in a selected group of 39 patients with no ring sideroblasts > and @5% bone marrow blasts treated with 13-cis-RA. Koeffler et aL" conducted a > randomized double-blind trial in which 68 patients received either 13-cis-RA > at a dose f I 00 Mg/M2/day or placebo for 6 months. There was no difference > between the two arms with regard to hematologic response, leukemic > progression, or overall survival. The dose of 1 3-cis-RA was relatively high > and not well tolerated. Dose limiting factors are hepatotoxicity with an > elevation of liver enzymes and hyperbilirubinemia. Addition of alfa-tocopherol > seems to improve the tolerability," although not improving the response rate. > Based on the impressive results in acute promyelocytic leukemia (APL), all- > trans-retinoic acid (ATRA) was studied in patients with MDS (Table 3).39- Used > as a single agent the results have been disappointing. An exception might be > the use of ATRA in patients with chronic myelomonocytic leukemia (CMML) where > it might reduce pancytopenia;' however, this suggestion stems from a pilot > study and consequently needsito be confirmed by a prospective randomized trial > . > > The role ofvitamin D3 analogues has been studied in several trials (Table 4)." > "No sustained hematologic effects were observed. At higher dosages, hyper- > calcemia and increases in the serum creatinine levels are the dose-limiting > adverse events. However, vitamin D3 derivatives might reduce the rate of > leukemic transformation either when used alone and in combination with low- > dose ara-C and 13-ci, retinoic acid." Further trials combined vitamin D3 with > 13-cis retinoic acid and - in the case ofincreased bone marrow blast cells - > with 6-thioguanine. Both a- and -y-interferon have been studied in sev-eral > clinical trials (Table 5). In general, the response rates have been low, and > only a few sustained responses, including complete remissions, have been > reported. The major adverse effect is myelosuppression. > > Hematopoietic growth factors which can also act through differentiation- > inducing mechanisms are dealt with separately below (see below Hematopoietic > growth factors section). > > While low-dose cytosine arabinoside was initially thought to act by inducing > differentiation, it is now generally accepted that its main mode of action is > suppression ofthe leukemic clone (see Lowdoseara-C in combination withgrowth > factors). Based on in vitro findings, the polar-planar solvent hexamethylene > bisacecamide (HMBA) was studied in two clinical trials > (Table 6). Several remissions were obtained, although the overall response > rate was low. > > A higher response rate wasobtained with 5-azacytidine which intracellularly > reduces the DNA methyltransferase activity and thereby leads to > hypomethylation. An overall response rate of47%, including 11 % complete > remissions, was found among 44 patients receiving a dosage of 75 mg/m@/day,@' > whereas less impressive results were obtained with lower dosages (Table > 6).61.11 Another analog, 5-aza-2'-deoxycytidine, induced a complete remission > in four out often patients.61 Newer approaches, which according to the authors > exert their action partially by differentiation induction, use > homoharringtonine. Trials combining various agents aim to take advantage of > additive or synergistic actions to induce differentiation. The results > ofcombining various hematopoietic growth factors, e.g. er),thropoietin with > either G-CSF or GM-CSF, will be presented separately. The combination of low- > dose ara-C with 13 cis-retinoic acid in 14 MDS patients was disappointing with > only one partial remission.'- Better results were seen after a combined > treatment with IFN-A, 13-cis-retinoic acid and vitamin D3 with a partial > response in 9 ofl 8 MDS patients." The combination ofATRA with G-CSF in 15 MDS > patients resulted in a com-bined transient increase ofplatelets and > neutrophils in 3 patients, while neutrophils increased in nearly all." The > addition of eryth,opoiecin and tocopherol to ATPA/G-CSF led to a trilineage > hematopoietic response in 6 outofl7 MDS patients.-' Patientswith an increase > in hematocrit also had an increase in their BFU-E numbers. > > Aminothiol amifostine, which in vitro can promote the formation and sumival > ofprimitive hematopoietic progenitors derived from MDS patients, has been > evaluated in a phase I/II trial. This study showed that amifostine > administered intravenously at doses 5 200 mg/m2 three times a week was well > tolerated and produced single- or multi-lineage hematologic responses in 15 > out of 18 MDS patients. > > Although leading to some encouraging results in vivo, the ways by which the > differentiation-inducing agents actually work, have remained largely > unresolved. Further clinical trials are necessary and should concentrate on > the low-risk groups of MDS, i.e. refi-actory anemia (RA) and RARS. Further > patient populations are the elderly not qualifying for the intensive > chemotherapy and stem cell transplancation. > > Hematopoletic growth factors > > Recombinant human etythropoletin > (rHuEpo) > > Anemia is a major clinical problem in MDS with many patients being adversely > affected by transfusion-dependency and secondary hemochromarosis. The phase > I/II studies on the use of rHuEpo in MDS have been previously reviewed. > Overall 1 5 to 20% of patients with myelodysplastic syndrome respond to rHuEpo > treatment but thevast majority of responders are not transfusion-dependent and > the doses required to achieve response are > 450 IU/kg per week. Factors > predicting response include serum erythropoietin levels < 100 mU/mL, female > gender, no or mild transfusion requirement and normal karyotype. MDS are stem > cell disorders, so that the typical anemic MDS patient is expected to have a > high serum Epo level, i.e. an appropriately increased endogenous Epo > production. It is therefore unclear why some individuals show inappropriately > low Epo levels, although it is now established that serum Epo reflects a > balance between renal production and erythroid consumption." > > Recognizing potential responde@ to rHuEpo can be excremely important in > individual cases ofMDS. In general, we favor a patient-oriented approach to > the use of rHuEpo where the physician care fully evaluates the individual > patient's needs and likelihood of reponse:" such approach can also be applied > to MDS patients. > > G-CSF, GM-CSF, IL,3 and IL-6 > > GM-CSF increases neutrophil counts in 64to 100% of treated patients. Other > types of white blood cells, particularly eosinophils and monocytes, also > increase in response to treatment. Interestingly, similar response rates were > found in studies using high doses (60-500 pg/m/day) and in those using low- > doses (0.2-0.5 pg/kg/day). One randomized study on GM-CSF versus observation > has been performed.' -@ As expected, neutrophil counts signifcantly increased; > hemoglobin levels and incidence of leukemic transformation were not influenced > while there was a clear decrease in platelet count in the GM-CSF treated > patients. The first preliminary report showed a tendency towards fewer > infections in the actively created group, but the study has not been reported > in fnal form. A positive effect ofGM-CSF on the frequency of infections has > also been suggested, however, this was not proven in another study. > > G-CSF has been used in a similar way as GM-CSF. A couple of phase I/II pilot > studies showed significant effects on neutrophil counts in the majority of > patients. Long-term results showed that neutrophilic response could be > maintained for up to 30 months." A randomized study between G-CSF and > observation showed a significant G-CSF induced increase in neutrophil counts > but no difference in hemoglobin levels and, as for GM-CSF, a signifcant > reduction of platelet counts.@' Overall survival and evolution to acute > myeloid leukemia (AML) were not influenced by treatment. The finding ofa > poorer survival in patients with refractory anemia with excess of blasts > (RAEB) treated with G-CSF was pobably relar- > ed to a higher proportion of high-risk patients in this group. Comparing GM- > CSF with G-CSF, side effects were milder during G-CSF treatment. GM-CSF tended > to give more general side effects such as flu-like symptoms, capillary leak > symptoms and local reactions at injection sites. > > With the aim of inducing trilineage responses in MDS, interieukin-3 (IL3) was > used in two phase I/II trials. Granulocyte counts increased in 40-78% of the > patients while hemoglobin values were unchanged. Some single patients had a > significant increase in platelet counts, while worsened thrombocytopenia was > observed in others. Treatment-induced fever was frequently observed. The > combination of GM-CSF and IL 3 was used in a small phase I study with > essentially negative results. > > Interleukin 6 was used in a phase 11 study of 22 patients with MDS and > thrombocytopenia. About one third of the patients showed increased platelet > counts, but reduced hemoglobin levels were observed in almost all patients and > the significant toxicity of the drugwas dose-limiting and prevented in most > cases long-term treatment. > > rHuEpo combined with G-CSF or GM-CSF > > Based upon the hypothesis that the addition of other cyrokines might improve > the response to rHuEpo, several clinical trials have studied the combination > of rHuEpo with G-CSF, GM-CSF or IL 3 (Table 7). > > The hitherto largest experience is with the combination ofG-CSF and rHuEpo. > The first two phase I/II pilot studies showed response rates of 38 and 42%, > respectively, suggesting that the response rate to this treatment was better > than that vath rHuEpo alone. Both studygroups then proceeded with enlarged > studies. Additional data 6-om the American study, showed that around 50% ofthe > patients with a response to the combination lost their response when G-CSF was > withdrawn and regained it when G-CSF was reintroduced. > > In a phase I I study 56 MDS patients were randomized to treatment with G-CSF > plus rHuEpo according to one of two alternatives: arm A starting with G-CSF > for 4 weeks followed by the combination for 12 weeks, and arm B starting with > rHuEpo for 8 week, followed by the combination for 10 weeks. The overall > response rate to G-CSF plus rHuEpo was 38% and there was no difference between > the two ams, Twenty patients entered long-term maintenance treatment and > showed a median duration of response of 24 months. These findings provide > evidence of an in vivo synergy between the two drugs. > > Four additional studies have examined the effects of G-CSF plus rHuEpo. In > two of these, results were comparable with the larger studies while two failed > to show a good response to treatment. The reason for this might have been the > lower rHuEpo dose used in these negative studies. Data from the Scandinavian > and American studies have recently been put together in a joint multivariate > analysis, showing that serum erythropoietin (<100 mU/mL, 500-1000 MU/mL or > > 500 mUlmL) and the level of pre-treatment transfusion needed (@ or @ 2 units > per month) are good predictors of erythroid response to treatment and may be > combined in a predictive model." The response rates in the good, intermediate > and poor groups were 74%, 23% and 7%, respectively. GM-CSF and rHuEpo have > been combined in for smaller phase 11 studies (Table7) In these studies, 5 > out of 23 patients with a documented lack of response to rHuEpo alone > responded to the combination. In a preliminary reported randomized phase 11 > study a synergistic effect ofthe two drugs was suggested in patients with > serum Epo values @ 500 MU/L lnterleukin 3 and rHuEpo show synergistic effects > in vitro but have not met with the Expectations in two reported preliminary > clinical studies. Only minor hematologic improvements have been observed > along with substantial adverse reactions including eosinophils and induction > of TNF-a. > > Low-dose chemotherapy > > The fact studies on treatment ofpeleukemia with low doses of chemotherapeutic > agents were published almost twenty years ago. The reasons for initiating > these studies included the extremely poor results of high-dose chemotherapy in > MDS patients at that time, and the hypothesis that low-dose chemotherapy might > act via different mechanisms than the higher doses and induce differentiation > of the malignant cells. > > Low-dose ara-C > > Low-dose ara-C has been extensively used in MDS (Table 8) and its mechanisms > of action have been widely discussed. A predominant cycotoxic effect was > proposed by some authors while others suggested the possibility of both > cytotoxic and differentiating effects. As suggested by recent studies, > induction of apoptosis is probably an important mechanism in this setting. In > the first clinical studies, response rates up to 71% were reported. This gave > rise to a series of smaller and larger phase II studies, which, however, never > could repeated the initial results. In these studies, the response rates > varied between 26-46%. Low-dose ara-C has mostly been given subcutaneously, > 10-30 mg/m2/day, divided into two daily doses for 2-8 weeks, but some of the > earlier studies used the intravenous route with comparable results. Very low > doses, down to 6 mg/m2/day, have also been tried with some effect. > > In 1987, Cheson and Simon reviewed the experience oflow-dose ara-C in MDS and > AML. In patients with primary MDS, complete and partial remission rates were > 17% and 19%, respectively, and in secondaryAML(including MDS-AML), 16% and > 14%. > > In a series of 102 Scandinavian patients with MDS or MDS-AML, the overall > response rate was 29% with a median duration of response of 8 months (range > 2-58 months). The response criteria were thougher in this study, since changes > in only blast or neutrophil counts were not defined as a response to > treatment. Multivariate analysis identified platelet counts, bone marrow > cellularity, chromosomal aberrations and ring sideroblasts as significant > predictive variables for response to treatment. Patients with platelet count > >15Ox IO 9/L had a response rate of 55% compared to 23.5% in patients with > subnormal platelet counts. Logistic regression identified low bone marrow > cellularity, absence ofring sideroblascs and < 2 chromosomal aberrations as > predictors of a favorable response in patients with platelet counts < 150xlO > 9/L. All these variables were combined in a predictive model for the use of > low-dose ara-C in MDS and MDS-AML. The model identifed three groups of > patients with 3%, 24% and @50 % response rate. This model is at present being > used in a prospective trial. > > Aul et al. compared survival of patients who had been treated with low dose > ara-C with another group treated with supportive care only, and found no > difference between the cwo groups. A randomized phase III trial comparing low- > dose ara-C with supportive care showed a response rate for ara-C of32% with a > median duration ofresponse ofS.9 months."' There was no difference in survival > between the two alternatives, but patiencs with active treatment showed a > tendency to a lower progression rate. The authors concluded that a > cytoreductive effect seemed to be required for a favorable effect. > > Although ifthis treatment is often initiated on an outpatient basis and > doesn't show side effects like nausea and alopecia, hematologic toxicity in > terms of bone marrow hypoplasia and pancytopenia may be pronounced. Therapy- > related death ranges from 15 to 20%. There is, however, a considerable > interpatient variation with regard to toxicity and the Scandinavian studies > showed a fatal toxicity of7%. > > Low-dose ara-C in combination with growth factors > > Low-dose ara-C has been combined with growth factors in a number ofstudies > (Table 8). The rationale for this was not only the treatment-induced cytopenia > caused by ara-C alone, but also the ability ofgrowth factors to recruit more > progenitors into the cell cycle, thus making them more susceptible to ara-C. > Ara-C and GM-CSF were combined in a couple of phase II studies showing that > the treatment was feasible and that it possibly reduced neutropenia due to > ara-C. The EORTC Leukemia Group then compared two alternative treatment > schedules in high risk MDS, one with ara-C and GM-CSF given sequentially and > one in which the drugs were partly given simultaneously. The total response > rate in 108 patients was 24%, there were 16% treatment-related deaths and no > difference between the two randomization arms. EORTC then continued with a > randomized phase III trial comparing low-dose am-Calone vs ara-C + GM-CSF vs > ara-C + IL3.' No statistically significant difference, between the three > alternatives were observed, response rates varied between 28 and 49% (highest > for ara-C alone) and survival varied between 10.5 to 24 months (lowest in the > GM-CSF group). The combination of G-CSF ad ara-C has only been used in one > small phase II trial in which seven out of 2l patients with MDS or MDS-AML > responded to treatment. > > Other chemotherapeutic agents given In low-doses > > Other chemotherapeutic agents have been employed in low doses in MDS patients > (Table 8). > > Low doses of an anthracycline, aclarubicin (ACR) were given to 15 patients > with MDS and MDS-AML, of whom 33% responded to treatments. The same > researches then continued with a small randomized phase II trial comparing the > effect of low-dose ACR with very low-dose ara-C. No significant differences > were observed between the two groups. The response rates in the ara-C and ACR > groups were 32% and 44% and the survival times 24 and 12 months, respectively. > > Another anthracycline, idarubicin, has been orally given in several phase If > trials. The first study used a relatively high dose, 50 Mg/M2, given with > 14-21 days intervals, and showed a response rate in 7/13 patients (54%). In > another study, the dose was 30-50 Mg/M2, and the response te 14%.13- Lastly, > Greenberg et al. used a very low dose, 2 mg/day for 21 days, but failed to > show a response in any except one of the 42 patients. These studies suggest > that oral idarubicin has a limited effect in MDS, unless given in clearly > myelosuppressive doses. > > Studies on the use of 5-azacytidine and homoharingtonine have been mentioned > before (Table 6). More interesting is a recently published study on low-dose > melphalan (2 mg/day until progression/toxicity or response) for patients with > high-risk MDS. Eight of 2l patients with RAEB or RAEB in transformation > (RAEB-t) (38%) achieved a complete (7) or partial (1) response with a median > survival of 27 months for CR patients and 6.5 months for the rest. No severe > side effects were observed in any patient. > > Chronic myelomonocytic leukemia is a proliferative entity of MDS in which the > proliferative symptoms have often been treated with hydroxyurea. A positive > report on the use of low dose etoposide in this subgroup preceded a large > randomized phase III trial on hydroyurea versus etoposide in 105 patients with > CMML. The results from this trial were surprisingly clear-cut in that > hydroxyurea in all aspects was better than etoposide. A response to treatment > was observed in 60% of the hydroxyurea patients versus 36% in those treated > with etoposide, and survival was significantly better in the former group. > However, the median survival in the hydroxturea group was only 20 months, > which is comparable to the survival observed in most prognostic studies. > Real treatment advances in CMML have thus not yet been achieved. > > In summary, low doses ofchemotherapeutic agents may be used to reduce bone > marrow blast counts and improve the pancytopenia in MDS and MDS-AML. > Hematologic complete remissions are observed, but patients are not cured and > there are no data showing a beneficial effect on survival in unselected groups > of patients. The larger studies show that the response rate is around 30% for > most ofthe agents but even if the median duration of response is often less > than one year, there are undoubtedly patients with long-lasting and stable > responses. Studies of low-dose am-C show that it is possible to define both > patients with a higher probabilicy of responding to treatment and those who > should not be treated. Such tools may prove use- > ful in the therapeutic decision for individual patiencs. Based on the present > experience, there is no evidence that routine addition ofvarious growth factor > either enhances or reduces the effect of low-dose chemo-therapy. > > Intensive chemotherapy > > Intensive chemotherapy is aimed at eradicating or suppressing the > myelodysplastic clone and thereby to induce long-term complete remission. The > first reports on successful treatment ofMDS patients with intensive > chemotherapy appeared in the early 1980s and have now been confirmed by many > othergroups (for a comprehensive review see Cheson and Gassmann et al.) (Table > 9). Apart from combinations of daunorubicin with either conventional or > high-dose ara-C, combinations of ara-C with idarubicin, idarubicin plus > etoposide, mitoxantrone plus etoposide, fludarabine plus ara-C, fludarabine > plus ara-C, as well as hematopoietic growth factors such as G-CSF, GM-CSF or > IL-3, have been tested in more recenttrials (Table 10 and I 1)."' "Although > reporting better results, the newer regimens have not yet been shown in > randomized trials to be superior to standard AML-type regimens. The same is > true for the CSFs, used either after chemotherapy or as priming agent together > with induction therapy. Similarly, the value of immunotherapy with > interleukin-2 as maintenance has still to be proven. > > While it was long assumed that CR rates are considerably lower in MDS than in > de novo AML, using an identical chemotherapy regimen, De Witte at al. achieved > an identical CR rate in patients younger than 45 years irrespective ofwhether > the patients had de novo AML or MDS (75% versus 71 %). More recent reports > also indicate that in patients above age 60 CR rates in the range of 50% to > 60% can be achieved (Table 1 0). The large variation ofcomplete remission > rates, ranging from 1 5% to 74% is probably related not only to the type of > chemotherapy and the dose intensity used, but also to differences in the > median age of the patients (due to better responses in the younger patients) > and to selection bias. The recent study by Estey etaL clearly indicates that > patients with RAEB and RAEB-T have the same chances of responding to > chemotherapy regimens as AML patients with similar prognostic factors. > Factors responsible forthe lower CR rates in MDS patiencs include drug > resistance ofthe neoplastic cell clone and, more generally a higher incidence > of poor prognostic characteristics. While achievement ofCR usually results in > the restoration of a polyclonal hematopoiesis, the median duration of complete > remission is usually short-lived and less than 12 months. Relapse-free > survival rates above 10% at 3 to 4 years are rare. > > Factors influencing CR rate, overall survival and relapse-free survival in > some but not all treatment series include patient age, presence or absence of > cytogenecic aberrations, and the diagnosis of de novo MDS or MDS after prior > exposure to leukemogenic chemotherapy. The presence of karyorypic > abnormalities which are frequently observed in MDS, including monosomy 7 and > 5q-, is associated with lower CR rates (31% versus 57%) and significantly > shorter remission duration (O% versus 25% at 3 years). Comparable data on the > influence of an abnormal karyotype have been reported by others. In > conclusion, the available evidence indicates that intensive chemotherapy based > on a combination of ara-C and an anthracycline should be proposed to all > patients with excess blasts, especially in those below 65 years ofage. > Deterrents to standard chemotherapy in these patients could include age and > abnormal cycogenetics. > > Stem cell transplantation > > While MDS is hard to cure with conventional therapies, cures have been > achieved with complete eradication of the marrow and replacement using stem > cells from a normal donor. Although restrictions based on patient age and > donor availabilicy limit the use of allogeneic stem cell transplantation (SCF) > to a small number of MDS patients, the potential for cure has encouraged > extensive investigation of this therapeutic option. > > Stem cell transplantation: > overview of large published series > > Between 1990 and 1997 twelve publications have described series ofgreater than > 20 patients with MDS undergoing allogeneic SCT (Table 12). A total of 516 > patients were reported in these 12 publications, including 64 whose disease > had progressed into AML before or at time of transplantation. Although there > was a wide variecy of patient characteristics and transplantation procedures > used, the major endpoincs ofrelapse and death were relatively similar between > these studies. There were 209 patients (41%) reported to be alive and disease- > free, with a median follow-up ranging from 11 months- > to 6 years, while 115 (22%) patients had relapsed and 192 (37%) had died of > transplant-related causes. A major conclusion from these data is that durable > cures, lasting up to 12 years, can be achieved in a significant fraction of > patients with an otherwise incurable hematologic disorder. A representative > example of disease-free survival (DFS) and relapse for the largest published > single-center study is shown in Figure 1, > > Two of the largest series reported results of multi-variable analyses. > Anderson et al found that both older age and longer disease duration were > independently associated with lower DFS, due to significantly higher non- > relapse mortality (NRM). More advanced disease morphology (beyond the phase of > refractory anemia) was associated with increased risk of relapse. In a follow- > up study with a larger number of patients, advanced disease morphology was > also significantly associated with lower DFS. Succon et al. reported that > increased marrow blast count was associated with lower DFS because of both > increased risk of relapse and NRM and that older age was associated with lower > DFS because ofincease risk ofrelapse.11 In addition, the use of cycoreductive > therapy before transplant (in 17 of 7l patients) was associated with a higher > risk of relapse, probably because such treatment was used mostly in patients > with RAEB-T. The association of age and survival has been reported in several > other series. > > Stem cell transplantation: > outcome by disease morphology and cytogenetics > > According to the French-American-British (FAB) classification, patients with > RA have fewer than 5% blasts in the marrow and 1% or fewer blasts in the > peripheral blood; whereas patients with RAEB or RAEB-T have increased blasts > in the marrow and/or peripheral blood. As outlined above, many studies of > allogeneic SCT for MDS have demonstrated that with increasing blast percentage > or advanced disease morphology (i.e., RAEB or RAEB-T compared with RA) them is > a higher risk of relapse post-transplantation, and, in some studies, a lower > DFS. A representative example of the difference in actuarial relapse rate and > DFS based on the FAB classification is shown in Figure 2. > > In this study the 5-year actuarial estimates of relapse and DFS were 49% and > 31%, respectively, for 47 patients with MDS with excess blasts (i.e., RAEB or > RAEB-t) compared with 4% and 54%, respectively, for 40 patients with MDS > without excess blasts (i.e., RA). > > Approximately 40% of patients with MDS at diagnosis have a clonal cytogenetic > abnormality, with complex abnormalities and chromosome 7 abnormalities being > associated with the shortest survival in the non-transplant setting. > Following allogeneic SCT, however, the prognostic significance of karyotype > has not been as clearly established as it has for morphology. In an initial > multivariable analysis of data from 59 patients from Seattle, the presence > ofan abnormal karyotype was associated with improved DFS and lower NRM. > However, this association of karyotype was not upheld in a subsequent > multivari- > able analysis ofthese 59 patients and an additional. In univariable analysis > of4O patients (daca was not available on the remaining 31 patients in the > study) from the French Bone Marrow Registry, patients with a single > cytogenetic abnormality had a statistically significantly lower risk of > relapse and higher DFS compared with patients with either normal karyotype > or complex abnormalities. However, this association did not emerge as a > significant finding in the multivariable analysis in that study. In a > univariable analysis from the European Bone Marrow Transplantation Group, in > which cytogenetic data were available from 54 patients, there was a lower > relapse rate among patients with a normal karyotype. More recent and larger > multivariable analyses of patients with MDS (excluding those who progressed > into secondary AML) have been reported in abstract form. One study of 25l > patients reported that patients with complex cytogenetic abnormalities had a > significantly higher risk of relapse and lower DFS and the other study of 338 > patients reported that a normal kayotype was associated with improved DFS. > Therefore, it is likely that cytogenetic features that are associated with a > poor survival in absence of transplantation are also independent predictors > of worse outcome following allogeneic transplantation. > > The association of poor risk cytogenetic features and relapse after allogeneic > SCT does not, however, appear to extend to patients transplanted with PA who > never progressed to a more advanced FAB morphologic classification. Only 1 of > 7O patients with RA (ofwhom 39 had cytogenetic abnormalities) relapsed, with a > median follow-up of approximately 3.5 years post-transplant. Similarly, > Sutton et al. reported no relapses among 11 patients transplanted with RA. In > these 2 studies, the long-term DFS rates among patients receiving human > leukocyte antigen (HLA)-identical related donor SCT were 74 and 73%, > respectively. Other studies have also corroborated the low risk of relapse > among patients transplanted for RA, despite the presence of cytogenetic > abnormalities (Table 12). > > Stem cell transplantation: > choice of stem cell donor > > Most patients transplanted for MDS have received marrow from HLA-matched > related individuals, but suitable related donors are only available to a > minority of patients who are otherwise eligible for allogeneic SCT. With > increasing size of the worldwide registries of HLA typed volunteer donors, the > potential use of unrelated donor transplantation is expanding. Results > published from Seattle on 52 patients with MDS or MDS-related AML transplanted > from unrelated donors show a 2-year actuarial DFS, risk of relapse, and risk > of NRM of 38%, 28%, and 48%, respectively. The risk of relapse was > significantly higher among patients with RAEB-T or MDS-related AML compared to > RA, RAEB, or CMML. The risk of NRM was significantly higher among older > patients and those with longer disease duration. At time of publication, 16 of > the 19 survivors had a performance status of 9O-l 00%. Registry reports on the > use of unrelated donor SCT in MDS patients have described a higher NRM and > lower DFS than the Seattle grouper but because of lack of detail it is not > possible to explore these differences. > Another study among patients with advanced disease morphology found that there > was a significantly lower risk of relapse among recipients of unrelated or > partially matched related donor marrow compared with recipients ofHLA-matched > related donor marrow. Two smaller studies which included a total of l9 > children with MDS undergoing unrelated donor SCT reported 10 disease-free > survival. > > These data suggest that the use ofalternative donors is feasible, but further > study is necessary to determine whether the long-term DFS is significantly > different from that of HLA-matched related donors. > > Stem cell transplantation: > preparative regimens > > The type of myeloablative preparative regimens used has varied between the > different series reported (Table 12). Because prospective, randomized studies > comparing different preparative regimens have not been reported, only > tentative conclusions can be drawn from existing data. The two most frequently > used regimens are cyclophosphamide and total body irradiation (CY-TBI) and > busulfan and CY (BU-CY). In a prospective, single-arm study of BU-CY in > patients with RA, the 3-year DFS rate was 63% and was similar to a group > ofhistorical controls treated with CY-TBI. Other single-arm studies using > BU-CY in patients with both RA and more advanced disease morphology have found > similar results to other published series in which predominantly CY-TBI > regimens were used. Two studies which included patients receiving regimens > containing BU-CY and additional chemotherapy found higher DFS than for > patients receiving CY-TBI or BU-CY alone, but small patient numbers and short > median follow-up (< 2 years) make definitive conclusions hazardous. Because of > the high risk of relapse among patients with advanced disease morphology, > regimens consisting ofTBI and intensified chemotherapy have been studied, and > have showed greater toxicity with no benefit in DFS. > > Stem cell transplantation: > therapy-related MDS > > Although the etiology of MDS is unknown in the majority of cases, an ncreasing > proportion of patients diagnosed with MDS have developed their disease > following treatment with chemotherapy or ionizing radiation or the combination > of both. Alky- > lating agents used for Hodgkin's and non-Hodgkin's lymphoma are the most > common drugs associated with development oftherapy-related MDS (t-MDS). T-MDS > typically develops 4-5 years following exposure to the inciting agent, and in > 90% of cases is associated with chromosome abnormalities, most commonly > involving chromosomes 5 and 7."' With increasing intensity of chemotherapy for > malignancies, such as autologous SCT for lymphoma, there appears to be an > increasing incidence of MDS.' A number of reports on SCT for MDS and secondary > AML have included patients with t-MDS and therapy- > related AML (t-AML)(Table 13). > > Table 13 outlines some ofthe available statistics from these reports. With > complete survival data on 135 of the 147 reported patients with T-MDS or T- > AML, 45 patients (33%) were disease-free survivors, 29 (22%) relapsed and 61 > (45%) died of transplant-related causes. These data suggest that allogeneic > SCT is a feasible treatment option for therapy-related myeloid malignancies, > but do not address the question of whether results are different from results > for patients with de novo MDS. In Seattle, 251 patients with MDS underwent > allogeneic SCT through 1996, 36 of whom had t-MDS. In multivariable > analysis, there was a significantly higher incidence of NRM among patients > with T-MDS compared with the remaining patients (relative risk 1.9, p-value > 0.014), but no difference in relapse rate or DFS (unpublished data, Anderson, > 1997). This finding of greater NRM, after adjustment for other factors known > to influence NRM, is not surprising and may be due to the cumulative toxicity > associated with treatment for the prior malignancy. > > Stem ceH transplantation: > timing of allogenic SCT > > The most appropriate timing for allogeneic SCT for MDS is not well defined. > Multivariable analysis from a Seattle study including all morphologic subtypes > found DFS to be better among patients with shorter rather than longer disease > duration due to lower NRM. However, in the multivariable analysis of the > French series there was no association becween disease duration and outcome. > It is possible that the effect of disease duration on DFS and NRM is more > important among patients with RA, since the association was found in the > multivariable analysis of 70 patients with RA,- but not in the analysis of 75 > patients with advanced disease morphology. As discussed above, patients with > fewer blasts and patients without poor risk cytogenetic features have an > improved DFS due to a lower risk of relapse. Therefore, we have generally > recommended consid- > eration of SCT early after diagnosis of MDS, before complications from > cytopenias develop, and, if possible, before the blast percencage increases or > karyotype evolves. However, there may be some patients with MDS who have a > particulariy indolent course, in whom early SCT might be ill advised. Patients > <= 60 years of age with a low risk International Prognostic Score have a > median survival of 11.8 years without transplantation. Therefore, because of > the early mortality associated with allogeneic SCT, some patients with low > risk MDS should probably not be advised to undergo early SCT. > > Stem cell transplantation. > current challenges in allogeneic SCT for MDS > > Innovative approaches to reduce the high risk of relapse after SCT among > patiencs with excess blasts with or without poor risk cytogenetic features are > needed. Current approaches include the use ofintensive chemotherapy before the > preparative regimen in an attempt to induce a morphologic and cytogenetic > remission, the development of more effective preparative regimens, and the use > of donor lymphocyte infusions after relapse. Retrospective comparisons of > patients transplanted without attempt at remission induction therapy or after > such treatment have resulted in contradictory results. Patients who fail to > obtain a complete remission after such chemotherapy, generally do poorly with > SCT. Patients transplanted after obtaining a complete remission were reported > to have a 60% 2-year DFS (n=16) in one study and a 43% 7-year DFS (n-7) in > another."' However, in the latter study, the improved outcome after SCr among > complete responders was due to a lower NRM, not a lower relapse rate. > Furthermore, as discussed earlier, no more than 60% of patients achieve a > complete response vath remission induction chemotherapy. Analysis of46 > patients with MDS-AML and t-AMLwho underwent SCT without an attempt at > induction chemotherapy showed a 24% 5-year DFS, which was not significantly > different from the 15% 5-year DFS of 20 patients who underwent SCT after > induction chemotherapy.'- Only prospective studies or large retrospective > studies that account for all patients receiving remission induction > chemotherapy (including those who die during such treatment or become > ineligible for SCT) will be able to address the use ofsuch pre-transplant > therapy definitively. > Evaluation of preparative regimens to reduce the risk ofrelapse is ongoing in > Seattle and elsewhere and includes the use of BU instead of CY along with TBI > and the addition of radionuclides conjugated to monoclonal antibodies directed > against hematopoietic cells. The use of donor lymphocyte infusions after > relapse (designed to induce a graft-versus-leukemia effect) has been reported > in 15 MDS patients, 7 ofwhom achieved a complete hematologic response with 6 > in remission between 2 and 18 months after infusion. > > The reason for the high NRM rate (approximately 40%) seen in patients with MDS > treated with allogeneic SCT is not well understood, but may be due to the > prolonged period of marrow failure preceding SCT. A reduction in the risk of > NRM is needed to improve outcome of currently eligible patients and, perhaps, > to expand eligibility ofallogeneic transplantation to older patients and to > those without currently suitable donors. Encouraging results using T-cell > depleted (10 3 -10 4 reduction) marrow in 11 patients with RA have been > reported. However, results using marrow depleted of T cells by counterflow > centrifugation (10 1 reduction) in a heterogeneous group of 35 patients, > including 11 with RA, do not appear to be better than those from series using > non-T-depleted grafts.' Alternative methods to reduce severity of graft- > versus-host disease and toxicity ofthe preparative regimen need to be > investigated. > > > Stem cell transplantation., > autologous SCT for MDS > > The use of autologous stem cells in transplantation for MDS is dependent on > the ability to collect non-clonal hematopoietic stem cells. The finding that > some MDS patients treated with remission induction chemotherapy can achieve a > complete morphologic and cytogenetic remission" suggests polyclonal > hematopoiesis can be achieved. X-linked clonalicy studies in females with MDS > have shown residual polyclonal hematopoietic cells either at steady state or > after chemotherapy. > Peripheral blood stem cell collections following chemotherapy have been shown > in some patients to be polyclonal based on X-chromosome inactivation patterns > or to be cytogenetically normal. A small number ofpatients have undergone > autologous SCT for MDS or MDS-AML (Table 14) and it appears that patients can > reliably engraft. Duration of follow-up in these studies is too short to make > meaningful conclusions about incidence of relapse, although NRM appears to be > relatively low. An important issue in the successful use of autologous stem > cells fi-om MDS patients following chemotherapy or other purging techniques is > the difficulty in detecting residual tumor contamination. It is not yet known > whether loss of a previous cytogenetic abnormality or demonstration of > polyclonality correlates with complete suppression ofthe neoplastic clonal > stem cell compartment. Further studies of autologous stem cell collection and > transplantation, including in vivo and ex vivo purging and detection of > minimum residual disease, are ongoing. > > Stem cell transplantation for MDS: > conclusions > > The heterogeneity of patients with MDS, the wide variety ofpatient inclusion > criteria and transplant procedures used, and relatively small numbers > ofpatients in the individual reports ofallogeneic SCr described in this > chapter make it difficult to draw many definitive conclusions. However, > approximately 40% of patientswith MDS are eligible for allogeneic SCT are > likely to be cured by this treatment. The most fortunate subgroup ofpatients > appears to be formed of those with RA who have an HLA-matched related donor, > in whom long-term DFS rates of approximately 75% have been achieved. > Currently, the major limitations in applying this treatment option to the > majority of patients are the advanced age of most patients with MDS and the > lack ofan HLA-compatible related or unrelated donor. In addition, the major > limitations to a greater success rate following allogeneic SCT are the > increased relapse rate among patients with increased blasts and poor risk > cytogenetic features and the increased NRM rate among patients with longer > disease duration, patients with t-MDS, and patients receiving mismatched or > unrelated grafts. The use of allogeneic SCT early in the disease course, if > possible, before increase in blast percentage, karyorypic evolution, or > complications of cytopenias develop may help improve outcome. Although a > subset of patients may benefit from the use ofremission induction chemotherapy > before the start of the preparative regimen, such pretransplant treatment has > not been conclusively shown to benefit the majority of patients who are at > high risk of relapse. In addition, no specific preparative regimen has been > conclusively shown to be preferable over others. The preliminary daca on the > use ofautologous SCT suggest this approach may be a feasible option for a > minority of patients, but the appropriate type of patient has not yet been > defined. In our opinion, some general recommendations for the use of > allogeneic SCT for patients with MDS can be made given the available data. > Patients up to 55 years of age should be evaluated at diagnosis for potential > and those with intermediate to high risk should be considered for > transplantation early after diagnosis while those with a low risk score should > probably be observed until evidence of disease progression. Patients between > 55 and 65 years of age should be considered in the context of clinical trials. > > lmmunosuppressive therapy > > In a recent study 25 transfusion-dependent MDS patients (with <20% blasts) > were treated in a phase II study with antithymocyte globulin (ATG) at 40 > mg/kg/d for four doses. Eleven subjects responded and became transfusion- > independent after ATG; median response duration was 10 months (range 3-38 > months). Biesma etal. reported similar response in two patients with > hypoplastic MDS treated with ATG and cyclosporin A. Randomized studies are > required to establish whether ATG can be effective in restoring hematopoiesis > in some MDS patients. Since aplastic anemia and hypoplastic MDS show many > similarities, it is possible that the latter also respond to immunosuppressive > therapy. > > Treatment of the Individual patient with MDS: > decision making by patient and physician > > Clinicians facing an individual patient with MDS should be aware of the fact > that the therapeutic choice is difficult and partly dependent on the patient's > expectations. Treatments proven to be effective in clinical trials are > summarized in Table 15. > We believe that any MDS patient should be given the following information: > a) the natural history of MDS is highly variable, ranging from a few > months to more than ten years, but most patients die because of disease- > related causes (complications of cytopenia, evolution into AML); > b) by using prognostic systems, e.g., the International Scoring System,' > it is possible to establish the individual's life expectancy with good > approximation; > c) the only known curative treatment at present is allogeneic stem cell > transplantation. Transplant-related mortality depends on the patient's age > and, perhaps, on the stem cell source (related versus unrelated donor) and > disease duration; in no case, at present, can it be considered negligible; > d) aggressive AML-like chemotherapy can restore normal polygonal > hematopoiesis and may cure a small portion of MDS patients with relatively > good prognostic factors (in terms of age and cycogenetics); > e) some treatmencs (supportive therapy in all individuals, rHuEpo + G-CSF > and low-dose ara-C in subsets of MDS patients) may improve the patient's > quality of life. Theoretically, some patients who benefit from these > treatments in terms of quality of life might also have prolongation > ofsurvival, but this is unproven. > > The fully informed individual patient will then be asked to participate in the > therapeutic decision. The approach we consider most appropriate based on the > evidence provided by clinical trials is that reported in Figure 3. We are > fully aware of the fact that many physicians will disagree with us, but still > feel that this approach may represent a useful starting base. Because ofche > inadequacies ofall current treatment modalities, participation in clinical > trials is encouraged. > > Since cytogenetic information is not available from at least 40% of MDS > patients, the IPSS' cannot be used in these individuals. Alternative > prognostic scoring system that are not based on cytogenetics should be used > in these cases to define the patient's risk. More generallyeach clinician > should use a prognostic scoring system that he or she is familiar with, and > classify the patient's risk as low, intermediate or high. > > Patients up to 55 years ofage should be evaluated at diagnosis for allogeneic > SCT, the major potentially curative treatment. > > Patients likely to experience a short-term unfavorable evolution (those with > an intermediated, intermediate-2, or high risk IPSS which will include > patients with either increased blasts or intermediate or poor risk cycogenetic > features) should be considered for transplantation (from an HLA-identical > Family donor or from a compatible unrelated donor) early after diagnosis. The > use ofsingle HLA antigen mismatched related or HLA-matched unrelated donor > grafts should be considered at institutions with favorable experience of using > such alternative donors. If no donor is available, AML-like chemotherapy > should be given. Such patients could also be considered for a clinical trial > with autologous SCT, if available. Those refusing aggressive chemotherapy can > be considered for low-dose chemotherapy orjust supportive therapy. Patients > up to 55 years of age with a low risk score should be observed until evidence > ofdisease progression, except, perhaps, in the case ofa single life- > threatening cytopenia or a particulary young individual with an HLA-matched > related donor. In any case, the patient's expectations prevail: he or she > should decide whether to undergo SCT with a risk of transplant-related > mortality in the order of 25-50% and a probability ofcure of5O to 75%. > Patients up to 55 years who do not have a donor or decide not to undergo SCT > can be offered a watchful-waiting strategy, or rHuEpo if Hb is below 10 > g/dLand serum Epo is below 100 mU/mL, or participation in trials on the use of > differentiating agents, or supportive therapy. When there is evidence of > disease progression, the patient should be offered SCT or AML-like > chemotherapy. > > For patients over 55 years ofage, risk of unfavorable evolution and > performance status represent the major factors for decision making. Patients > between 55 and 65 years of age with an intermediate or high risk, a good > performance status and an HLA-identical family donor should be considered for > allogeneic SCr in the context ofclinical trials. lfno donor is available, > participation in a clinical trial of autologous SCT should be considered. > Patients between 55 and 75 years of age with a good performance status should > be given AML-like chemotherapy. > > Patients with poor performance status and/or over 75 years of age should > routinely be given supportive therapy. > Patients over 55 years of age with a low risk score can be offered a watchful- > waitingstrategy, orrHuEpo if Hb is below 1 0 g/dL and serum Epo is below 100 > mU/mL, or participation in clinical trial on the use of differentiating > agents, or supportive therapy. When there is evidence of disease progression, > the patient should be treated as patients ofcomparable age with intermediate > to high risk. > > ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ > -Please discuss information found through AA-MDS-TALK with your > hem-oncologist before making any treatment related decisions. > > -Visit the AA-MDS-TALK Web Page below for additional information such as > how to change your subscription options, how to view the archives, and how > to unsubscribe from the list (send e-mail to listserv@listserv.aol.com with > "signoff aa-mds-talk" in the body of the message without the quotes!) > > http://www.concentric.net/~vmwlbw/aa-mds/Index.htm > ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ > > ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -Please discuss information found through AA-MDS-TALK with your hem-oncologist before making any treatment related decisions. -Visit the AA-MDS-TALK Web Page below for additional information on how to change your subscription options, how to view the archives, and how to unsubscribe from the list (send e-mail to listserv@listserv.aol.com with "signoff aa-mds-talk" in the body of the message without the quotes!) http://www.concentric.net/~vmwlbw/aa-mds/Index.htm -To utilize AOL's interactive AA-MDS-TALK web page visit http://listserv.aol.com/archives/aa-mds-talk.html
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