Therapy-Related Myelodysplastic Syndromes



Therapy-Related Myelodysplastic Syndromes

Therapy-related myelodysplastic syndromes are increasing in frequency as the utilization of intensive chemotherapy and radiation increases in other solid tumors and lymphoma.36–43 These cases have a poor prognosis and are not included in the International Prognostic Scoring System (IPSS). Cellular abnormalities of chromosomes 5, 7, and 8 are common in these cases.317 MDS following breast cancer is associated with older age, presence of other cancers, and multiple first-degree relatives with cancer.318 As compared to patients with myeloma or germ cell tumors, patients with lymphoma undergoing autologous stem cell transplantation have a higher incidence of treatment-related MDS. In this group, pretransplantation therapy, total-body irradiation, and other transplantation-related factors play a role, as do inherited polymorphisms in genes governing drug metabolism and DNA repair.319 Therapy-related MDS has been reported after high-dose melphalan for myeloma treatment, but the risk is relatively low.320 Accelerated telomere shortening precedes development of therapy-related myelodysplasia after autologous transplantation for lymphoma.321 Treatment-related MDS is managed as are de novo cases of MDS, but are very refractory to treatment. Allogeneic hematopoietic stem cell transplantation can result in long-term disease-free survival, but most patients with therapy-related MDS are not candidates because of advanced age, comorbidities, or the inability to control the primary cancer.322

Treatment of Myelodysplastic Syndrome Based on Prognostic ScoreTherapeutic decisions in MDS patients can be based on the category of disease, such as 5q– syndrome or clonal anemia. These approaches are outlined after each category of specific syndrome. Because the syndromes are a continuum and have irregular manifestations, an IPSS was devised to assign patients at the time of diagnosis to a category that estimates the likelihood of early progression, the average time by which patients with those characteristics will evolve to AML, and incorporates information beyond the MDS subtype.277,279,309 Multivariate analysis combines the impact of (1) percentage of marrow blasts, (2) three cytogenetic subgroups (favorable, unfavorable, intermediate), and (3) number of cytopenias (Table 88–3). In large numbers of patients, the following frequency distribution of patients has been observed: low-risk group (i.e., longest time to evolve to AML) in 15 to 30 percent of patients; intermediate-1 risk group in 30 to 40 percent of patients; intermediate-2 risk group in 20 to 25 percent of patients; and high-risk group in 5 to 10 percent of patients.277,279,323

Table 88–3. International Prognostic Scoring System for Myelodysplastic Syndromes277
Prognostic Variable Score Value
0 0.5 1.0 1.5
Marrow Blast (%) <5 5–10 11–20
Karyotype Good Intermediate Poor
Cytopenias 0, 1 2, 3
Risk groups: Low, 0; INT-1, 0.5–1.0; INT-2, 1.5–2.0; High, ≥2.5.Karyotype: Good score, -Y, del(5q); poor score, complex abnormalities and chromosome 7 abnormalities; intermediate score, other abnormalities. See “Marrow: Cytogenetics” above for further details.

Using the IPSS to classify patients, survival is worse as risk category increases in four defined groups from low-risk to high-risk (Table 88–4), and this effect is influenced by age at diagnosis within the same prognostic category (Table 88–5).

Table 88–4. Survival of Patients with Clonal Cytopenias and Oligoblastic Myelogenous Leukemia Based on the International Prognostic Scoring System
IPSS Score at Diagnosis No. of Patients 2-Year Survival 5-Year Survival 10-Year Survival 15-Year Survival
Low 267 85% 55% 28% 20%
Intermediate-1 314 70% 35% 17% 12%
Intermediate-2 179 30% 8% 0
High 56 5% 0
IPSS, International Prognostic Scoring System.These data were extrapolated from curves in Figure 6 of reference 277. Data are expressed as percent of all patients in that risk category surviving at the time interval shown.
Table 88–5. Survival of Patients with Clonal Cytopenias and Oligoblastic Myelogenous Leukemia Based on the International Prognostic Scoring System Stratified by Age
IPSS Score and Age 2-Year Survival 5-Year Survival 10-Year Survival 15-Year Survival
Low ≤60 years 95% 80% 65% 30%
Low >60 years 80% 45% 18% 18%
Intermediate-1 ≤60 years 85% 50% 37% 18%
Intermediate-1 >60 years 62% 30% 12% ND
Intermediate-2 ≤60 years 50% 15% ND
Intermediate-2 >60 years 25% 5% 0
High ≤60 years 0
High >60 years 7% 0
IPSS, International Prognostic Scoring System; ND, no data.These data were extrapolated from curves in Figure 7 of reference 277. Data are expressed as percent of all patients in that risk category surviving at the time interval shown.

The prognostic score should not be the sole guide to treatment because many patients deviate from the average expectation of disease behavior. Unexpected progression may necessitate changes in treatment approach and in the case of patients who are candidates for allogeneic hematopoietic stem cell transplantation; their course may require recommending the procedure. Furthermore, several refinements to the original IPSS score have been proposed to incorporate factors such as ALIP and CD34 expression,324 duration of MDS and prior therapy,325 and lactate dehydrogenase.326,327 Also, other time-dependent prognostic scoring systems have been proposed, including the WHO Prognositc scoring System.328 Although these systems have benefit in defining populations and allowing comparisons between defined groups, they are often of little aid in making treatment decisions in individual patients and in understanding the biology of MDS.329

Treatments based on the IPSS can be considered (1) supportive care, (2) low-intensity therapy, or (3) high-intensity treatment.330–332 Treatment response is judged based on the MDS subtype and IPSS score of the patient and the presence of treatment-induced (secondary) MDS.333

Therapy for Patients with Low and Low-Intermediate (Int-1) Prognostic Scores

Supportive care consists of improving quality of life with specific treatment of cytopenias or their complications and providing psychosocial support, while monitoring the patient’s clinical status at intervals.334,335

Management of Anemia

Red Cell Transfusion

Red cell transfusions should be administered for symptomatic anemia. Often patients will tolerate hemoglobin levels as low as 8 g/dL, but the level at which symptoms develop varies from patient to patient. Higher thresholds have been suggested to prevent cardiac consequences of prolonged anemia.336

Erythropoiesis-Stimulating Agents

Red cell transfusion dependency may have a negative impact on clinical outcomes in MDS probably related to more severe marrow failure in those cases, increased iron overload, and possibly correlation with increased risk of transformation to AML.337 Some studies found that neither the serum ferritin nor the number of red blood cell transfusions impacted survival in clonal sideroblastic anemia.338 Recombinant erythropoietin can be used to treat anemia in patients who are transfusion-dependent, if the serum erythropoietin level is low for the hemoglobin level. Responses are best with low erythropoietin levels, normal blast counts, lower IPSS scores,339 normal cytogenetics,340 and in patients who do not require transfusion.341 Hemolysis, or iron, vitamin B12, or folate deficiency should be ruled out as a cause of anemia before erythropoietin therapy is started. Iron stores should be kept replete during erythropoietin therapy. Erythropoietin 150 to 300 U/kg per day or single weekly doses of 40,000 U are effective.340 Darbepoetin alpha in various schedules of administration has also been found effective in increasing hemoglobin levels and in enhancing quality of life.343,344 The probability of a response increases with duration of therapy; for example, optimal at 26 weeks compared to 12 weeks.345 Meta-analysis has confirmed erythropoietic response rates are similar for those treated either with epoetin alfa or with the longer-acting darbepoetin alfa.346 Unlike the case in patients with solid tumors or renal failure, there is no evidence that erythropoietic agents increase thromboembolic disease or accelerate progress to leukemia, but followup in these studies has been short.347 G-CSF combined with erythropoietin may produce a response more frequently.348,349 This combination does not appear to affect the risk of leukemic transformation and may have a positive impact on survival in those with low transfusion needs.350 This approach is not recommended for those with intermediate-2 risk or high-risk IPSS scores.351 There is evidence that marrow erythroid cells of MDS patients who respond to erythropoietin have a different gene expression pattern than do those of nonresponders.352

Iron-Chelation Therapy

Chelation may be necessary to prevent iron overload in patients receiving frequent transfusions. Numerous consensus guidelines have been published regarding the treatment of iron overload in myelodysplastic syndromes.353–355 These emphasize that there is no prospectively validated threshold for (1) the number of units of transfused blood or (2) the level of serum ferritin that should trigger iron chelation.355 Several of these guidelines use a serum ferritin >1000 mcg/L as a threshold for starting iron-chelation therapy. They also take into account the patient’s candidacy for allogeneic stem cell transplantation, life expectancy, and evidence of iron-related organ damage.355 Both deferoxamine given subcutaneously or intravenously and deferasirox given orally are available for chelation therapy in MDS patients.356 Cardiac magnetic resonance imaging may provide more reliable means of assessing myocardial iron overload than does measurement of serum ferritin.357

Low-Dose Cytarabine

Low-dose cytarabine 5 to 20 mg/m2 per day by subcutaneous injection every 12 hours for up to 8 to 16 weeks or by continuous intravenous infusion has been used in lieu of intensive chemotherapy.358,359 Although this approach led to remission in approximately 20 percent of patients with oligoblastic leukemia, the median duration of remission is approximately 10 months, and survival has not been prolonged compared with supportive care alone. Moreover, low-dose cytosine arabinoside usually is cytotoxic, inducing marrow hypoplasia and worsening cytopenias. Although occasional reports of remission following low-dose cytarabine have been consistent with an effect on leukemia cell maturation, most patients experience suppression of the malignant cell clone, leading to marrow repopulation with polyclonal hemopoiesis.304,309,330 This treatment approach is now utilized less often since the advent of other FDA-approved agents for MDS, but may still have a role in some patients, especially when combined with G-CSF.360


Cyclosporine and Antithymocyte Globulin

In some patients with MDS, T-lymphocyte–mediated inhibition of hematopoiesis occurs and contributes to cytopenias. The cytopenias can be ameliorated by treatment with immunosuppressive agents.361 In patients who recovered effective hematopoiesis after treatment, the V (T-cell receptor-) spectra-type representative of clonal or oligoclonal T-cell populations reverted to normal patterns.361 A nonclonal X-chromosome inactivation pattern in the marrow, as assessed by the human androgen receptor gene assay and the phosphoglycerated kinase-1 assay, was associated with a response to ATG. This finding was attributed to incomplete clonal expansion, with ATG improving normal hematopoiesis by relieving the immunologic pressure on the remaining normal progenitors.362 Others have postulated that responses may result from suppression of interferon- secretion by CD4+ T cells.363 Some series have reported response rates to ATG of 15 to 60 percent364–366 and longer survival times in patients who respond. Human leukocyte antigen (HLA)-DR15 (DR2) is overrepresented in MDS and predicts a response to immunosuppressive therapy.367 In one series of 60 patients treated with ATG and cyclosporine, 60 percent had hematologic improvement, and more responders had good karyotype or DRB1 1501.368 Most of the patients in this series had refractory anemia and an IPSS score of intermediate-1. Most, but not all, responses have occurred in patients with hypocellular marrows.369,370 In a series of 129 patients who were treated with immunosuppressive therapy at a single institution, 30 percent had either a complete or partial response, and younger age and intermediate or low IPSS score favored survival.371 Other groups have reported lack of response to ATG and prednisone. One study was stopped early because of lack of efficacy and development of adverse reactions.372 Other studies also have reported lack of efficacy of single-agent cyclosporine.373

Other Treatment Options in Low- or Intermediate-1–Risk Patients

For those patients not likely to respond to supportive care measures alone or for those who are not likely to respond to immune suppressive therapies, azacytidine, decitabine, or lenalidomide can be used. In those not responding to these approved agents, in appropriate patients, allogeneic stem cell transplantation or other investigational options can be considered (see Hematopoietic Stem Cell Transplantation).

Therapy for Patients with High-Intermediate (Int-2) Prognostic Scores

Demethylating Agent and Histone Deacetylation Inhibitor Therapy

Oligoblastic and secondary myelogenous leukemias have a high prevalence of tumor suppressor gene hypermethylation.374 5-Azacytidine is a pyrimidine analogue that inhibits DNA methyltransferase, reduces cytosine methylation, and induces maturation of some leukemic cell lines. It also is an antiproliferative drug. Administration of the drug and its congener decitabine has resulted in improvement of some patients with oligoblastic leukemia.267,375 5-Azacytidine at a dose of 75 mg/m2 once per day given subcutaneously for 7 consecutive days each month provided significantly more frequent benefit to two-thirds of patients than did supportive care. Quality of life was enhanced, and disease progression was delayed.267,275,376 Complete responses were seen in approximately 15 percent of 5-azacytidine–treated patients, and up to 36 percent had hematologic improvement.375 Ninety percent of responses were seen by cycle 6. In another series,377 subclasses of MDS did not predict for response to 5-azacytidine. A decrease in the white blood count during the initial cycle correlated with a higher response rate. 5-Azacytidine was approved by the FDA in 2004 for treatment of all subtypes of myelodysplastic syndrome. Treatment with this agent can usually be accomplished on an outpatient basis,378 and intravenous379 and oral formulations have been examined.380 Other schedules of administration to accommodate outpatient therapy have been reported to have benefit but have not been directly compared to the 75 mg/m2 daily dose for 7 days every 4 weeks.381

5-Aza-2′-deoxycytidine (decitabine) is also FDA approved for all MDS risk categories. Seventeen percent of patients in one series had a major cytogenetic response on an intention-to-treat basis after a median of three courses. The median duration of cytogenetic response was 7.5 months in all IPSS groups.382 Patients who responded had improved survival compared with patients in whom the cytogenetically abnormal clone persisted.383,384 A 5-day intravenous schedule was found to be optimal in one series, which examined several schedules of administration385; examination of optimal doses and schedules continues.386 Decitabine probably works partly through demethylation, as it has resulted in demethylation of a hypermethylated p15/INK4B gene in patients.383 Demethylation was associated with clinical responses.384 Oligodeoxynucleotide antisense approaches to DNA methyltransferase-1 inhibition are also being explored in MDS.387

Inhibitors of histone deacetylation may have activity in MDS and are under investigation. Numerous agents are being studied and include depsipeptide, butyrate derivatives, suberoylanilide hydroxamic acid, and valproic acid.388 Phase I trials have been completed in MDS with LBH589, a cinnamic hydroxamic acid analogue389 and with MGCD0103.390 There is interest in combining histone deacetylation inhibitors with DNA methyltransferase inhibitors.391

Management of Thrombocytopenia

Thrombocytopenia is common in MDS and has a higher prevalence in higher-risk IPSS categories.392 Furthermore, many therapies used in MDS may exacerbate thrombocytopenia. Platelet transfusions may be required if the platelet count falls below 10 x 109 cells/L or in support of chemotherapeutic-induced thrombocytopenia. Antifibrinolytic agents such as aminocaproic acid can be used in patients who have bleeding despite platelet transfusion or to decrease the need of platelet transfusions.393 Low-dose IL-11 is being studied as a means of increasing the platelet count in patients with symptomatic thrombocytopenia as are thrombopoietin-receptor agonists. AMG-531 (Romiplostim) and Eltrombopag may increase platelet counts in a subset of MDS patients394–396 and are under investigation for this purpose.

Neutropenia, Fever, and Infections

Granulocyte-Stimulating Factors

Randomized, double-blind studies have not shown that any cytokine prolongs survival or reduces morbidity in oligoblastic leukemia. GM-CSF and G-CSF397–399 increase neutrophil counts and functions in some patients. G-CSF receptor expression may be low in some patients with MDS and prevents a good response to endogenous or administered G-CSF.400 Complete remissions have been reported in hypoplastic AML/MDS with G-CSF alone.401 Granulocyte transfusions are rarely used in MDS.402 Rare serious complications, such as splenic rupture, have been reported with use of G-CSF.403 Cytokines do not delay progression to acute leukemia; however, they increase the percentage of blasts in the blood in a proportion of patients, an event that is not always reversible with cessation of cytokine.397,398 In one review, 22 of 83 reported cases of myelodysplasia treated with G-CSF or GM-CSF had an increase in marrow blast percentage, and AML evolved in 12 of 69 patients. An increased percentage of abnormal macrophages has been reported.404 Use of these agents without chemotherapy in oligoblastic leukemias carries a risk of promoting expansion of leukemic blast cells.405 Combinations of growth factors alone or coupled with maturing agents have not significantly improved response or survival rates.406,407


Febrile events are common in higher-risk syndromes because of the frequency of moderately severe neutropenia and functional disorders of neutrophils and monocytes. Also, chemotherapy is more likely to be used in these situations, inducing severe neutropenia. Careful cultures and use of broad-spectrum antibiotics until and if a specific organism are found is important (see Chap. 20).

Therapy for Patients with High-Intermediate (Int-2) or High-Risk Prognostic Scores

Demethylating Agent Therapy

Patients in higher-risk IPSS categories can be treated with demethylating agents if they are not suitable candidates for allogeneic hematopoietic stem cell transplantation. In one study of higher-risk MDS patients where 5-azacytidine was compared to conventional care regimens that included supportive care, low-dose cytarabine treatment, or intensive induction chemotherapy, 5-azacytidine increased survival as compared to standard care regimens.408 With the exception of allogeneic hematopoietic stem cell transplantation, however, all of these treatments are palliative.409

Acute Myelogenous Leukemia Chemotherapy

Chemotherapeutic regimens containing standard doses of cytarabine, an anthracycline antibiotic, and/or etoposide (see Chap. 89) result in remission in fewer than 20 percent of patients with high-risk MDS. Moreover, a proportion of patients become worse with intensive chemotherapy. The advanced age and the high frequency of cardiac, renal, immunologic, and other organ system impairment in most patients with oligoblastic leukemia are largely responsible for the poor outcome. Patients who are younger than age 60 years have higher remission rates of up to 50 percent410 and can be considered for intensive therapy. Patients older than age 60 years have a median survival of only 9.5 months with this approach and the survival is reduced to 4 months in those with unfavorable karyotypes, indicating a lack of benefit in this group.411 In addition to the standard combination of anthracycline and cytarabine, other regimens, such as liposomal daunorubicin and topotecan with or without thalidomide, did not result in clinical benefit in patients with AML or high-risk MDS.412 The so-called FLAG-Ida regimen (fludarabine, cytarabine, idarubicin, and G-CSF) resulted in 53 percent complete remissions and 11 percent improvement in 45 patients with high-risk myeloid malignancies, 13 of whom had MDS.413 Gemtuzumab ozogamicin (Mylotarg), which is approved for treatment of relapsed AML in elderly patients, has not been useful for treatment of MDS.414,415

Hematopoietic Stem Cell Transplantation

Allogeneic Stem Cell Transplantation

This approach has been used to treat various MDS in patients ranging in age from 1 month to older than 70 years.416–418 It remains the only treatment with curative potential for MDS. Conditioning regimens have consisted of cyclophosphamide plus irradiation or busulfan plus cyclophosphamide. Most patients have received transplants from histocompatible sibling donors, although some experience with partially mismatched, related, and unrelated donors has been reported. A good representation of the results of this traditional approach using marrow stem cells is a study of 93 patients (age range: 1 month to older than 60 years; median age: 30 years).419 The most favorable results were seen in patients younger than age 40 years with shorter duration of disease and with less than 5 percent blast cells in the marrow at the time of transplant. These patients may have a disease-free survival of 60 percent at 4 years and an overall disease-free survival estimated at 40 percent. Older patients had higher peritransplantation mortality and relapse rates. Actuarial relapse probability at 4 years was 30 percent for the entire group and 50 percent for patients with greater than 5 percent marrow blasts. Cytogenetic abnormalities did not predict outcome in this study, but adverse cytogenetics were an important prognostic factor in other studies. With targeted busulfan therapy, stem cell transplantation can be successfully performed in patients as old as 66 years of age.420,421 Numerous factors such as disease stage, patient age, comorbidities, prior therapies, type of donor, and source of stem cells need to be weighed when recommending stem cell transplantation to MDS patients.

An International Bone Marrow Transplant Registry report of 452 patients with MDS who received allogeneic transplantation found that young age and platelet counts greater then 100 x 109/L prior to transplantation were associated with lower transplantation mortality, higher disease-free survival, and overall survival. Patients with higher percentage of blasts and high IPSS scores had higher relapse rates.422 Blood or marrow stem cell sources can be utilized. One report showed superior results with mobilized blood versus marrow stem cells.423

The National Marrow Donor Program transplantation experience in MDS included 510 patients. Median age was 38 years, and the probability of disease-free survival at 2 years was 29 percent (confidence interval [CI] 25–33%). The 2-year incidence of treatment-related mortality was 54 percent, which was the major barrier to success in this patient population.424 Unrelated cord blood transplantation for adult and pediatric patients with MDS has been successfully performed,425 but results with unrelated marrow donors are inferior to the results of matched sibling transplants. It is anticipated that these results will improve in the era of high-resolution HLA matching between donor and recipient.426

Stem cell transplantation for MDS should be performed before the disease progresses to AML.427 When T-cell depletion is used to prevent graft-versus-host disease, the best outcomes occur in those who are transplanted while in remission.428 Poor cytogenetics may impact risk of relapse but not nonrelapse mortality.429 In one retrospective series, blast percentage less than 5 percent at time of transplantation was the best predictor of improved disease-free survival, and myeloablative conditioning was associated with lower relapse risk but could not overcome increased disease burden.430 Patients with secondary MDS have comparable outcomes after stem cell transplantation as those with de novo MDS when high-risk cytogenetics are considered.431,432 Pretransplantation neutropenia is also associated with inferior outcomes as a result of infection-related mortality.433 Prior therapy with demethylating agents does not appear to increase the toxicity of transplantation and whether it will improve outcomes by decreasing disease burden remains to be studied systematically.434 The morbidity and mortality of various transplantation approaches remain high, and some patients are not candidates for ablative transplantation because of age or comorbid conditions.435

Reduced-intensity conditioning with allogeneic hematopoietic stem cell transplantation from HLA-identical family members or unrelated donors has been examined for MDS treatment.436 In one series of 16 patients (median age: 54 years) receiving a conditioning regimen of fludarabine and cyclophosphamide, no day 100 transplantation-related mortality was observed, and the 2-year actuarial event-free survival was 56 percent (CI 30–68%). Other fludarabine-containing conditioning regimens have been reported.437,438 One series compared reduced intensity to standard transplantation in MDS patients and noted similar 2-year overall and disease-free survival with different patterns of toxicity.439 In some series, patients older than 70 years of age have undergone transplantation440; the future role this will play in therapy of older MDS patients is under investigation.441 For those patients who relapse after reduced-intensity stem cell transplantation, salvage therapy with donor lymphocyte infusions, second transplantations, or chemotherapy may be feasible.442,443

Autologous Stem Cell Infusion

Patients with oligoblastic leukemia have been infused with their own stem cells after intensive chemotherapy.444 The approach may be limited by contamination of the stem cell product with a repopulating leukemic cell and the absence of a graft-versus-leukemia effect. The absence of a graft-versus-host reaction makes the approach more applicable to the age group usually affected. In selected patients, peritransplantation mortality with intensive therapy and stem cell rescue has been approximately 10 percent, and approximately 50 percent of selected patients had extended survivals.445 The more advanced the disease at the time of treatment, the worse the outcome. With the increasing use of reduced-intensity allogeneic transplantation, autologous stem cell transplantation has been used less often. Interestingly, when autologous transplantations for AML are performed in patients with antecedent myelodysplasia, no impact on stem cell mobilization or hematopoietic recovery has been noted.446

Other Therapies in Use or under Study in MDS

Other Single-Agent Cytotoxic Drugs

Hydroxyurea and low-dose etoposide are useful in controlling leukemic cell proliferation but usually produce only partial responses and do not influence survival duration.331 Occasional patients have achieved remissions with etoposide (50 mg as a 2-hour infusion, two to seven times weekly for 4 weeks; or 100 mg/day orally for 3 days and then 50 mg twice weekly).447 Low-dose melphalan,448 gemcitabine,449 CPT-11, a DNA topoisomerase I inhibitor,450 troxacitabine, an enantiomer of cytarabine,451 and weekly doses of oral idarubicin452 have each resulted in responses in some patients. Clofarabine, a purine nucleoside analogue, has activity in MDS.453 Oral topotecan has only modest activity in MDS.454 ABT-751, a microtubule inhibitor, is being studied in MDS.455

Antiangiogenesis Agents

Thalidomide has shown effectiveness in MDS therapy.456 Patients receiving 100 to 400 mg/day for 12 or more weeks had no cytogenetic or complete responses, but 16 patients had hematologic improvement.457 In another series of 34 patients in whom 400 mg/day was the median dose tolerated, 6 patients had progressive disease, 4 patients had stable disease, and 11 patients had partial remissions (5 major responses and 6 minor responses), accounting for a 56 percent response rate. Hematologic improvement was not noted until after a median of 2 months.458 Cytogenetic responses have been seen in cases of monosomy 7, the 5q– syndrome, and with complex karyotypic abnormalities. Although thalidomide has antiangiogenesis activity, it also decreases vascular endothelial growth factor and basic fibroblast growth factor levels.459 The drug may have a particular role in patients with marrow fibrosis.460 Thromboembolic events have occurred in patients receiving thalidomide in combination with darbepoietin-.461

The thalidomide derivative lenalidomide (Revlimid) lowers levels of proangiogenic cytokines, inhibits attachment of stromal cells, promotes cell-cycle arrest and apoptosis, and affects function of natural killer and cytotoxic T lymphocytes. In patients who have chromosome 5q deletion, lenalidomide has been found to reduce transfusion requirements and reverses cytogenetic abnormalities.462 In patients without deletion 5q, reduction in transfusion requirements occur in approximately 43 percent with some patients becoming independent of transfusions. This trial included only low- or Int-1–risk MDS,463 whereas 5q– patients who have high-risk MDS can show responses. Additional cytogenetic abnormalities limit the responses.464 Unlike the case with thalidomide, dose reduction for myelosuppression often was required, and myelosuppression appears to be lenalidomide’s primary toxicity.465 In those patients with 5q deletion, cytopenias during therapy may be indicative of a response.466

Anti-Tumor Necrosis Factor Therapy

The soluble TNF receptor fusion protein etanercept (p75 TNFR:Fc) has produced mixed results in MDS. In one pilot series, moderate improvement in cytopenias was noted,467 whereas in another trial, no responses were noted in 10 patients.468 In another pilot study of 3 months duration, one patient became transfusion independent temporarily, but overall efficacy was low.469 The chimeric anti–TNF- monoclonal antibody infliximab resulted in two sustained erythroid responses (one major and one minor), and a decreased percentage of apoptotic cells in the marrow.470 It is anticipated that therapies such as TNF inhibitors, which inhibit apoptosis, might be useful in low-grade MDS, whereas in high-grade MDS, therapies that promote apoptosis might be more effective.471

Agents that Alter Oxidation State

Amifostine has had minimal activity in MDS.472 TLK199, a glutathione analogue inhibitor of glutathione S-transferase has resulted in hematologic improvement in early phase studies473 and is still undergoing evaluation.

Retinoids, Vitamin D Derivatives, Arsenic Trioxide, and Other Potentially Maturation-Enhancing Agents

Glucocorticoids, vitamin A analogues (retinoids), vitamin D analogues (dihydroxyvitamin D3), pyrimidine analogues (cytarabine), hexamethylene bisacetamide, and interferon are among other agents that can induce in vitro maturation of mouse and human leukemic cells.474–476 Use of cis-retinoic acid, 20 to 100 mg/m2, isotretinoin, 25 mg/m2, or ATRA, 45 mg/ m2, orally given daily for up to 3 months, has produced only slight, transient (few weeks) improvement in a very small proportion of patients with oligoblastic leukemia.477,478

A combination of low-dose cytarabine, retinoic acid, and 1,25-dihydroxyvitamin D3 in 44 patients with oligoblastic leukemias produced 50 percent response rates, with longer survival in responders than in nonresponders.479 Hexamethylene bisacetamide given intravenously at a dosage of 20 to 24 g/m2 per day for 10 days, followed by an 18- to 75-day observation period, resulted in increased neutrophil counts and reduced marrow blasts in 4 of 16 patients with oligoblastic leukemia.480 In another study, no responses were observed.475 Sodium phenylbutyrate is an agent that has shown some activity against oligoblastic leukemia and is in clinical trials.481

Arsenic trioxide, used as a single agent, results in responses in approximately 20 percent of cases.482 Low-risk MDS patients are most likely to show benefit.483 Whether the drug affects cell maturation, apoptosis, or proliferation in this disease remains to be determined.484–486

Tyrosine Kinase and Other Cell-Signaling Inhibitors

Imatinib mesylate, the tyrosine kinase inhibitor of ABL, KIT, and platelet-derived growth factor receptor, has not resulted in clinical responses in patients with MDS.487,488 Inhibitors of RAF protein kinase such as sorafenib,489 and inhibitors of farnesyltransferase such as lonafarnib,490 tipifarnib,491,492 and BMS-214662,493 have been examined in MDS. Statins that inhibit geranylgeranylation are being studied for treatment of AML and MDS.494 Agents such as bortezomib, which indirectly target nuclear factor-B, are being examined in MDS,495–497 as are agents which target mTOR (mammalian target of rapamycin).498 Progenitors involved in MDS rarely express FLT-3 mutations,499 so FLT-3 inhibitors are not thought to be useful in the treatment of MDS.

Uncommon Acquired Syndromes with Increased Risk of Acute Myelogenous LeukemiaAmegakaryocytic Thrombocytopenia

Amegakaryocytic thrombocytopenia may be congenital, associated with MPL gene mutations, or acquired,500,501 and are both very uncommon preleukemic syndromes (<1%), although bona fide cases have transformed into AML months or years after diagnosis.502,503 Among 1220 cases of MDS, 11 cases of isolated thrombocytopenia were associated with clonal chromosome abnormalities, usually involving chromosome 3, 5, 8, or 20. Antiplatelet antibodies were not present, and glucocorticoids were ineffective. Five of the 11 patients progressed to acute myelogenous leukemia (Table 88–6; see Chap. 119).502

Table 88–6. Hypocellular Marrow Syndromes that May Precede Onset of Acute Myelogenous Leukemia
Amegakaryocytic thrombocytopenia (Chap. 110)
Chronic hypoplastic neutropenia (Chap. 65)
Apparent aplastic anemia with evidence of clonal hematopoiesis (Chap. 34)
Paroxysmal nocturnal hemoglobinuria–aplastic anemia syndrome (Chaps. 34 and 40)

Isolated Neutropenia

Acquired, isolated, chronic neutropenic states are very rare antecedents of AML. Congenital neutropenia can evolve into AML.504 The latter evolution is associated with mutations in the G-CSF-receptor (CSF3R) gene (see Chap. 65). Evolution of Shwachman-Diamond syndrome (neutropenia and exocrine pancreatic insufficiency) into oligoblastic or overt acute leukemia has been documented.505 The related disorder, Pearson syndrome (sideroblastic anemia, neutropenia, and exocrine pancreatic insufficiency), is a preleukemia disorder in children (see Chap. 34).506

Chronic Monocytosis

In a small proportion of patients, unexplained persistent monocytosis may be the most striking blood cell abnormality for months or years before development of acute leukemia.122–124

Aplastic Anemia, Paroxysmal Nocturnal Hemoglobinuria, and Eosinophilic Fasciitis

AML or MDS occurs in a proportion of patients with acquired aplastic anemia.507,508 Since the advent of immunotherapy, the propensity to myelodysplasia and leukemia has increased, partly because of the greater longevity of patients and the often incomplete restitution of hematopoiesis. Patients who initially responded to immunosuppressive therapy have later developed MDS (see Chap. 34 for a discussion of the interrelationship among aplastic anemia, MDS, and paroxysmal nocturnal hemoglobinuria).509

Paroxysmal nocturnal hemoglobinuria is a clonal stem cell disease that often is associated with marrow hypoplasia (see Chap. 40). AML may ensue in approximately 0.5 percent of patients. It is a clonally derived syndrome with a low incidence of leukemic transformation relative to other clonal myeloid diseases. All chronic clonal hemopoietic stem cell disorders (e.g., polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis, chronic myelogenous leukemia) have a propensity to undergo clonal evolution to AML (see Chap. 85). Patients with indolent myeloid clonal disorders may have a paroxysmal nocturnal hemoglobinuria-like defect of their blood cell membranes.

Eosinophilic fasciitis mimics the cutaneous manifestations of scleroderma. Symmetrical swelling and induration of arms and legs, sparing the hands and feet, are common.510,511 Eosinophilia and hypergammaglobulinemia are frequent. Immune cytopenias, aplastic anemia, myelodysplasia, AML, and lymphoma have been associated with the disease.512 An immune mechanism has been postulated for all the disease manifestations. The risk of developing AML is greatly increased compared with healthy individuals.510–512 Marrow transplantation has been used to treat the aplastic anemia.513

Prodromal Syndromes Antedating Lymphocytic LeukemiaThe indolent clonal disorders usually imply conditions that are an antecedent of myelogenous leukemia. A significant proportion of cases of AML are preceded by MDS. Even in de novo AML many cases have protracted periods of symptoms and signs before onset. ALL usually begins explosively, and symptoms rarely are present for more than a few weeks prior to diagnosis (see Chap. 93). Intermediate syndromes (e.g., smoldering or oligoblastic lymphocytic leukemia or prodromal anemias) are rare, but the latter have been reported, occasionally in children,514 but especially in adults who develop ALL.515–521

Apparent aplastic anemia522–526 or erythroid hypoplasia527 has been described as an antecedent to ALL in approximately 2 percent of childhood cases and much less commonly in adult cases. The aplasia is promptly improved by glucocorticoids, and ALL ensues soon, usually within 1 to 8 months. The brief interval between remission of aplastic anemia and onset of leukemia suggests the leukemia, although inapparent on marrow biopsy, in some way initiates the aplasia.522,528 Remission of aplasia followed shortly by ALL has occurred in the absence of glucocorticoid or other specific therapy in several cases. The aplastic marrow prodrome of ALL may be distinguishable by its very high prevalence in females (approximately 90%), high prevalence of fibrosis on marrow biopsy (approximately 90%), frequent marrow lymphocytosis (approximately 60%), and spontaneous, temporary recovery (>90%).529

Indolent Clonal Myeloid Disorders or Oligoblastic (Myelogenous) Leukemia Preceding or Emerging in Lymphoid Malignancies Other Than Acute Lymphocytic LeukemiaSideroblastic anemia sometimes associated with qualitative disorders of other blood cell lines (such as thrombopathy) has developed in patients who had, or later developed, a lymphoproliferative disease, such as hairy cell leukemia, lymphocytic lymphoma, myeloma, chronic lymphocytic leukemia, or Hodgkin lymphoma.530–538 The sideroblastic anemia in these cases was not preceded by cytotoxic therapy. Similar associations have been reported in patients who received chemotherapy or radiotherapy for a lymphoproliferative disease or a solid tumor and who later developed a preleukemic syndrome presumed to result from the prior treatment. Other types of myelodysplasia can occur concurrent with B- or T-lymphocyte–derived tumors.530–539

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