Lenalidomide

The Management of Multiple Myeloma in Younger Patients

September 19, 2013 Chemotherapy, Cytogenetics, Hematology, Therapeutics, Transplantation No comments , , , , , , , , , ,

Therapy for multiple myeloma (MM) has advanced with gratifying speed over the past 5 to 7 years and with this progress, a degree of uncertainty has arisen about optimal approaches to therapy, particularly in the newly diagnosed patients. Indeed, using mordern therapeutic strategies, living with MM for a decade or longer has now become a reality for a significant proportion of patients.

Pathophysiology

MM is characterized by neoplastic proliferation of plasma cells involving more than 10% of the bone marrow. Increasing evidence suggests that the bone marrow microenvironment of tumor cells plays a pivotal role in the pathogenesis of myelomas.

The malignant cells of MM, plasma cells, and plasmacytoid lymphocytes are the most mature cells of B-lymphocytes. B-cell maturation is associated with a programmed rearrangement of DNA sequences in the process of encoding the structure of mature immunoglobulins. It is characterized by overproduction of monoclonal immunoglobulin G (IgG), immunoglobulin A (IgA), and/or light chains, which may be identified with serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP).

The role of cytokines in the pathogenesis of MM is an important area of research. Interleukin (IL)–6 is also an important factor promoting the in vitro growth of myeloma cells. Other cytokines are tumor necrosis factor and IL-1b.

The pathophysiologic basis for the clinical sequelae of MM involves the skeletal, hematologic, renal, and nervous systems, as well as general processes.

Development Progresses

Skeletal processes

Plasma-cell proliferation causes extensive skeletal destruction with osteolytic lesions, anemia, and hypercalcemia. Mechanisms for hypercalcemia include bony involvement and, possibly, humoral mechanisms. Isolated plasmacytomas (which affect 2-10% of patients) lead to hypercalcemia through production of the osteoclast-activating factor.

Destruction of bone and its replacement by tumor may lead to pain, spinal cord compression, and pathologic fracture. The mechanism of spinal cord compression symptoms may be the development of an epidural mass with compression, a compression fracture of a vertebral body destroyed by multiple myeloma, or, rarely, an extradural mass. With pathologic fracture, bony involvement is typically lytic in nature.

Hematologic processes

Bone marrow infiltration by plasma cells results in neutropeniaanemia, andthrombocytopenia. In terms of bleeding, M components may interact specifically with clotting factors, leading to defective aggregation.

Renal processes

The most common mechanisms of renal injury in MM are direct tubular injury, amyloidosis, or involvement by plasmacytoma.[14, 15] Renal conditions that may be observed include hypercalcemic nephropathy, hyperuricemia due to renal infiltration of plasma cells resulting in myeloma, light-chain nephropathy,amyloidosis, and glomerulosclerosis.

Neurologic processes

The nervous system may be involved as a result of radiculopathy and/or cord compression due to nerve compression and skeletal destruction (amyloid infiltration of nerves).

General processes

General pathophysiologic processes include hyperviscosity syndrome. This syndrome is infrequent in MM and occurs with IgG1, IgG3, or IgA. MM may involve sludging in the capillaries, which results in purpura, retinal hemorrhage, papilledema, coronary ischemia, or central nervous system (CNS) symptoms (eg, confusion, vertigo, seizure). Cryoglobulinemia causes Raynaud phenomenon, thrombosis, and gangrene in the extremities.

Workup

Some tests can afford important prognostic information and the subtypes of myeloma. These tests include classic CRAB measurements (calcium level, renal function, amemia, bone damage) , β2-microglobulin, albumin, lactate dehydrogenase (LDH), serum and urine monoclonal protein (24-hour) such as serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE), 24 h urine protein electrophoresis (UPEP), urine immunofixation electrophoresis (UIFE), and so on, serum-free light chain assay.

Bone marrow examinations such as morphology, FISH (fluorescent in situ hybridization) analysis of key genetic events, metaphase cytogenetics are also mandatory at present.

Table 1. Genetic Tests to Be Performed in Myeloma Patients at Diagnosis.

With these tests, multiple myeloma can be divided into three subtypes, which are solitary plasmacytoma, smoldering myeloma (asymptomatic myeloma) and active myeloma (symptomatic myeloma).

Subtypes of Multiple Myeloma

According to the latest NCCN guideline MM can be categorized into three subgroups including solitary plasmacytoma, smoldering myeloma (asymptomatic), and active myeloma (symptomatic).

Solitary plasmacytoma

Solitary plasmacytoma is a large solitary focus of plasma cell proliferation. To simplify, solitary plasmacytomas can be divided into 2 groups according to location: Plasmacytoma of the skeletal system (SBP) or Extramedullary plasmacytoma (EMP). Similarly, the latest NCCN guideline for MM categorizes solitary plasmacytoma into solitary osseous or solitary extraosseous.

Criteria for identifying solitary bone plasmacytoma (SBP) vary among authors. Some include patients with more than one lesion and elevated levels of myeloma protein and exclude patients whose disease progressed within 2 years or whose abnormal protein persisted after radiotherapy. With the use of magnetic resonance imaging (MRI), flow cytometry, and polymerase chain reaction (PCR), the currently accepted criteria are as follows:

  • Single area of bone destruction due to clonal plasma cells
  • Bone marrow plasma cell infiltration not exceeding 5% of all nucleated cells
  • Absence of osteolytic bone lesions or other tissue involvement (no evidence of myeloma)
  • Absence of anemia, hypercalcemia, or renal impairment attributable to myeloma
  • Low, if present, concentrations of serum or urine monoclonal protein
  • Preserved levels of uninvolved immunoglobulins

Diagnostic criteria for extramedullary plasmacytoma (EMP) are as follows:

  • Tissue biopsy showing monoclonal plasma cell histology
  • Bone marrow plasma cell infiltration not exceeding 5% of all nucleated cells
  • Absence of osteolytic bone lesions or other tissue involvement (no evidence of myeloma)
  • Absence of hypercalcemia or renal failure
  • Low serum M protein concentration, if present

Smoldering myeloma

Smoldering myeloma describes a stage of disease of MM with no symptoms and no related organ or tissue impairment. According to the latest version of NCCN guideline for MM, criteria for the definition of smoldering myeloma are as follows:

  • M-protein in serum ≥30 g/L and/or
  • Bone marrow clonal plasma cells ≥10%
  • No related organ or tissue impairment (no end organ damage, including bone lesions) or symptoms.

Note that the M-protein refers to the monoclonal protein produced by MM cells.

Active/symptomatic myeloma

Criteria for the definition of active/symptomatic myeloma requires one or more of the following:

  • Calcium elevation (>11.5 mg/dL) [>2.65 mmol/L]
  • Renal insufficiency (creatinine >2 mg/dL) [177 µmol/L or more]
  • Anemia (hemoglobin <10 g/dL or 2 g/dL < normal)
  • Bone disease (lytic or osteopenic)

In the section of management of MM we will discuss the specific therapeutic approaches for these three subtypes of MM.

Prognosis and Genetics

Several factors can afford important prognostic information for multiple myeloma. They are β2-microglobulin, lactate dehydrogenase (LDH), cytogenetics, and plasma cell-specific FISH analysis (hyperdiploidy, t(4;14)(p16;q32), t(14;16)(q32;q23), 17p13, t (11;14)(q13;q32), 1q amplifications, 1p deletions, loss of 12p, gains of Cr5).

Table 2. Risk Classification Based on Baseline Testing

Of note that in the latest NCCN guideline about multiple myeloma several high-risk chromosomal aberrations in MM locates at 14q32, including three main ones that are t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Thus the risk incidence of t(11;14) is inconsistent with what was decribed in Table 2.

For this inconsistent two view I have sent an inquiry to NCCN and their answer was “We have reviewed your inquiry with the NCCN Guidelines Panel Chair, Dr. Kenneth Anderson. NCCN does not classify t(11;14) as high risk, it is only listed as a major group containing the 14q32 translocation. ”

And pay attention that patients with t(4;14), β2 microglobulin <4 mg/L and hemoglobin ≥10 g/dL may have intermediate risk disease.

Although the genetics can afford the prognosis of multiple myeloma, this approach still needs more evidence. At present the method is still the Durie-Salmon criteria or ISS criteria.

Table 3. Stage of Multiple Myeloma

As shown in the table 2 at left, the stage of multiple myeloma can be divided into three periods: stage I, stage II, and stage III.

The Management of Solitary Plasmacytoma

For those patients with osseous plasmacytoma, primary radiation therapy (45 Gy or more) to the involved field is the initial treatment and is potentially curative. Extraosseous plasmacytomas are treated initially with radiation therapy (45 Gy or more) to the involved field followed by surgery if necessary.

After radiation thearpy, patients with solitary plasmacytoma need follow-up. Blood and urine tests performed every 4 weeks initially to monitor response to the primary radiation therapy. If the patient achieves complete disappearance of the paraprotein then the frequency could be reduced to every 3-6 months or as indicated clinically. If the protein persists, then the monitoring should continue every 4 weeks. These tests include CBC, serum chemistry and those listed in the section of workup.

If progressive disease emerges, then the patient should be re-evaluated for recurrent plasmacytoma or myeloma, and systemic therapy administered as indicated.

The Management of Smoldering Myeloma

Although the activity of novel agents has advanced to the point that early interventions are now being explored in clinical trials for smoldering myeloma, there is still no evidence that early treatment will improve survival in asymptomatic and biochemically stable patients. A critical point is that up to 25% of smoldering myeloma patients will not require active treatment for 10 to 15 years. However, the majority will indeed progress during that time.

Once diagnosed, smoldering myeloma patients require frequent monitoring to allow treatment to begin before end-organ damage is evident. These tests are similar with solitary plasmacytoma, which are listed in the section of workup. If the disease progresses to symptomatic myeloma, these patients should be managed as active/symptomatic myeloma. We will discuss the management of active/symptomatic myeloma below.

The Management of Active/Symptomatic Myeloma

If the patients with MM progresse to active/symptomatic myeloma. Treatment should be initiated. Generally, we divide the treatment strategy into initial drug therapy, hematopoietic cell transplantation, and consolidation and maintenance thearpy after transplantation.

Therapeutic goal

There is a growing body of evidence showing an association between depth of response to therapy and improved long-term outcomes, including progressive-free survival (PFS) and overall survival (OS), in MM patients. Using conventional chemotherapy, it has been shown that there is a correlation between response before and after transplantation and that the quality of response after transplantation has a marked impact on outcome.

Importantly, studies suggest that if a patient achieves a complete response (CR), this must be durable and that the duration of CR is the best predictor of OS. However, some special cases makes the view that initially obtaining a CR in predicting long-term outcome questionable, for instance, group of rapidly responding but early relapsing patients, group of more indolent myelomas that revert to an “monoclonal gammopathy of uncertain significance like” profile after therapy, and group of myeloma patients with stable nonprogressive disease after induction therapy.

Initial drug therapy

Although success and long-term remission have been achieved in many transplantation-eligible patients using limited treatment regimens, such as thalidomide/dexamethasone, bortezomib/dexamethasone, and lenalidomide/dexamethasone, complete and very good partial response (VGPR) rates can be substantially increased by combining these various drugs in triplets or even using 4 drugs together.

On the right is the data of several clinical trials. I list all the detail of regimens below:

VAD: vincristine, adriamycin, and dexamethasone;

TD: thalidomide and dexamethasone;

RD: lenalidomide and dexamethasone;

PAD: bortezomib, doxorubicin, and dexamethasone;

VTD: bortezomib, thalidomide, and dexamethasone;

CVD: cyclophosphamide, bortezomib, and dexamethasone;

RVD: lenalidomide, bortezomib, and dexamethasone;

CVRD: cyclosphamide, bortezomib, lenalidomide, and dexamethasone.

A note of caution is that many of these studies are based on relatively small numbers of patients at single, or limited numbers, of centers, but cumulatively the message is consistent, with frequent, rapid, and deep responses seen.

Althought response rates are clearly improved with new drug cocktails, proving a consequent OS advantage is difficult and especially challenging given the large numbers of patients and the long duration of follow-up required. However, based upon response rates, depth of response achieved, and PFS as surrogates, 3-drug cocktails are currently the modality of choice in clinical practice, with use of RVD, CVD, or VTD as the most commonly chosen regimens outside of clinical trials.

Transplantation

Transplantation is a useful modality helping achieve or consolidating CR. But is it necessary to provide any consolidation chemotherapy before transplantation? If the patient is going to proceed to  transplantation, when do we implement the transplantation. However, because the goal of therapy is to maximize the depth and duration of remission, induction therapy can be continued in some patients for as long as the patient is responding and tolerating therapy, which might be instead of transplantation.

Generally ASCT is the primarily way of transplantation. Allo-SCT should infrequently be performed outside of clinical trials, as the risk of morbidity and early mortality of even nonmyeloablative transplantations is considerable.

Question one is whether to offer any consolidation chemotherapy before transplantation.

After initial induction thrapy, the subsequent approach is to provide further 4 to 6 cycles of induction threapy, then proceed eligible patients to ASCT. The reason to use stem cell transplantation is to provide a consolidation of remission after obtaining the best possible response to frontline treatment.

But a controversial area is what to do if the patient has already achieved a CR before transplantation. In this decision, the role of continued chemotherapy treatment versus proceeding to transplantation is less clear and an are of active research. Generally, in practice we prefer to proceed patients to transplantation without any further induction chemotherapy.

The reason to proceed to transplantation even achieving CR before transplantation is that current measures of CR are insufficiently sensitive and residual disease is in many, if not all, patients present but below the level of detection.

Question two is when do we offer stem cell transplantation to our patients who are eligible to this procedure. The timing of ASCT is also an area of active research. Patients are usually more fit for intensive therapy early in the course of the disease, but prior studies using conventional chemotherapy as induction demonstrated this a delayed ASCT had no adverse impact on OS and is feasible as part of salvage therapy in first relapse.

Maintenance therapy

Clinical studies found thalidomide maintenance to improve overall survival. Lenalidomide may offer the same advantages with less toxicity. Generally, it has become our practice to use maintenance routinely when patients have not achieved a CR after stem cell transplantation or when genetic risk markers suggest a very high risk of early relapse.

Figure 1. Respond Criteria for Multiple Myeloma

The Management of Myelodysplastic Syndromes (MDS)

June 21, 2013 Chemotherapy, Cytogenetics, Hematology, Pharmacotherapy, Therapeutics, Transplantation 3 comments , , , ,

The myelodysplastic syndromes (MDS) are a collection of myeloid malignancies characterized by one or more peripheral blood cytopenias. MDS are diagnosed in slightly more than 10,000 people in the United States yearly, for an annual age-adjusted incidence rate of approximately 4.4 to 4.6 cases per 100,000 people. They are more common in men and whites. The syndromes may arise de novo or secondarily after treatment with chemotherapy and/or radiation therapy for other cancers or, rarely, after environmental exposures. De novo MDS is called primary MDS while the other is called secondary MDS. Indeed, the natural history of secondary MDS is expected to be worse than primary MDS. In this post we mainly focus on primary MDS and any recommendations for therapies here should be interpreted with caution when considering patients with secondary MDS.

Risk and Prognosis

There are three scoring system to evaluate the risk and prognosis of myelodysplastic syndromes (MDS) including: IPSS (International Prognostic Scoring System, 1997), WPSS (the WHO classification-based Prognostic Scoring System), and IPSS-R (Revised-IPSS, 2012).

IPSS (table 1) is the most widely used classification system for patients with MDS. 3 factors including the percentage of bone marrow myeloblasts, the diagnostic cytogenetics, and the number of cytopenias are used to generate a prognostic score. However, there are some limitations of IPSS: 1. the lack of inclusion of secondary (after prior cytotoxic therapy) MDS cases, 2. the inclusion of many patients now considered to have AML, 3. the lack of “treated” cases, and 4. the unknown impact of currently available therapies.

Table 1. The International Prognostic Scoring System (IPSS) for MDS.

Score
Prognostic variable00.51.01.52.0
Bone marrow blasts (%)< 55-1011-2021-30
Cytogenetics*GoodIntermediatePoor
Cytopenias, n0 or 12 or 3

 

ScoreIPSS subgroupMedian survival (years)
0Low5.7
0.5-1.0Int-13.5
1.5-2.0Int-21.2
> 2.5High0.4

*Good: normal, -Y, del(5q), del(20q); intermediate: other abnormalities; poor: complex (≥ 3 abnormalities) or chromosome 7 anomalies.
†Platelets < 100,000/μL; hemoglobin < 10 g/dL; neutrophils < 1,800/μL.

Reproduced from Greenberg P, et al. Blood. 1997;89:2079-88 © 1997 by The American Society of Hematology.

WPSS (table 2) makes use of the WHO subclassifications and supports the intuitive notion that the need for red cell transfusions predicts for a worse prognosis. The risk groups of WPSS are very low (0 point), low (1 point), intermediate (2 points), high (3 to 4 points), or very high (5 to 6 points). The median survival and risk of progression to AML at 5 years is 140 months/3%, 66months/14%, 48 months/33%, 26 months/54%, and 9 months/84%, respectively. Note that two categories of RAEB were recognised by the WHO classification, in which RAEB-1 and RAEB-2 with 5-9% and 10-19% blasts, respectively.

Table 2. WHO classification-based Prognostic Scoring System.

WHO classification-based Prognostic Scoring System for MDS.

In IPSS-R (table 3) bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation.

Table 3. Revised-IPSS

Compared with IPSS, the IPSS-R model showed effective separation of the IPSS patient risk categories and more effectively discriminated prognostic risk for these patients than the IPSS. Data indicated that 99% of the patients in the IPSS-R Very low and Low risk subgroups encompassed those who had been classified as IPSS Low and Intermediate-1; 81% of those in the IPSS-R High and Very high risk subgroups had been classified as IPSS Intermediate-2 and High.

The Management of MDS

After the evaluation of risk and prognosis, comes the management of MDS. Which patient should be treated and how?

Figure 1. Approach to Therapy of MDS Patients

Myelodysplasia is an incurable disease with non-transplantation therapy, but highly variable in its natural history. Treatment considerations must take into account many factors, including the pathologic diagnosis, the prognosis based on the IPSS, WPSS, or IPSS-R, the unique disease features in that particular patient, feasibility of performing a clinical trial, the appropriateness of a bone marrow transplantation, and indeed the philosophy of the patient and the family concerning his or her care.

In addition, if the patient has secondary MDS, tolerability of therapy is probably worse because of previous exposure to DNA-damaging agents and predicting how patients with secondary MDS will respond is difficult because of a lack of data and exclusion of such patients from most clinical trials.

Until now MDS remains a challenge for clinicians because of the older patient milieu, the disease heterogeneity, and the lack of effective medical therapy. And the choice between therapies is hampered by a relative lack of prospecitve randomized trials.

Firstly, what we should do after evaluation is to determine whether to treat or not. There are patients who have MDS based on sound pathologic and clinical criteria who might best be served by observation. Treatment should be reserved, and potentially the diagnosis transmitted to the patient and family, only if there are symptoms resulting from anemia or other cytopenias or perhaps presymptomatic anemia or severe thrombocytopenia.

Once the decision to treat is made, different approaches are available. However, we don’t know the standard algorithm beacuse lack of prospective randomized trials. We lack of effecive therapeuitc approach for this disease at present.

Supportive Care

Supportive care includes blood components transfusion, treatment of neutropenia and possible infections, and bone marrow stimulation.

Patients with moderate-to-severe anemia require RBC replacement. Transfusing packed RBCs for severe or symptomatic anemia benefits the patient temporarily, only for the life span of the transfused RBCs (2-4 wk). Patients with congestive heart failure may not tolerate the same degree of anemia as young patients with normal cardiac function, and slow or small-volume (eg, packed RBCs) transfusions with judicious use of diuretics should be considered.

Patients with multiple RBC transfusions might develop transfusion-induced iron overload which can incur significant damage of the liver, heart, pancreas, and other tissues. Current guidelines recommend starting iron chelation therapy in those patients who have received 20-25 units of packed RBCs or who have a serum ferritin level of >1000 μg/L. However, there are absolutely no definitive data concerning the frequency of such complications, let alone whether patient outcomes might be improved by the use of chronic iron chelation therapy. Tow iron chelation agents have been approved by FDA for the indication of iron overload: deferoxamine and deferasirox.

The notion of using hematopoietic growth factors to treat the cytopenias of patients with MDS is attractive but certainly limited by the problem of an intrinsically deranged and therefore potentially unresponsive marrow stem cell. Nonetheless, virtually every patient with MDS and anemia at some point receive an erythropoietic growth factor. However, there is incomplete information and confusion about the likelihood of response, the optimal dose, and whether to use a short- or long-acting agent. 25% of patients with anemia will respond (reduce their transfusion requirement by at least 50% or increase hemoglobin by 1g/dL) and response can take 8 weeks or more. It is common practice to increase the dose of erythropoietic growth factor once or even twice before concluding that the patient is unresponsive to single-agent erythropoietin. Patients who are not ransfusion dependent at baseline or who have relatively low intrinsic levels of serum erythropoietin (< 500 mIU/mL) are more likely to respond with response duration in 1 to 2 years. Lack of response could be the result of insufficient iron stores, but the presumptive usual problem is an intrinsically unresponsive marrow. The hemoglobin response to erythropoietin may be improved from 25% to 40% with the addition of low-dose granulocyte colony-stimulating factor.

Platelet transfusion is beneficial to stop active bleeding in thrombocytopenic patients, but the life span for transfused platelets is only 3-7 days. Routine use of platelet transfusions to support nonbleeding (even severly) thrombocytopenic patients is not advisable. The ASCO clinical guideline for prophylactic platelet transfusion also suggests that many of these patients can be observed without prophylactic transfusion, reserving platelet transfusion for episodes of hemmorrhage or during times of active treatment.

There are no useful currently available cytokines for thrombocytopenic MDS patients.

Neutropenia without a history of infection is a poor justification for initiation of therapy. Randomized studies did not demonstrate any real clinical benefit of granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. If neutropenia with infection, manage patients with board-spectrum antibotics necessary. If with systematic serious fungal infection antifungal agents should be given.

Transplantation

The HSCT is the only modality to cure this disease. But it dose not mean every patient diagnosed with MDS should be referred for such a procedure. Patients can reasonably safely be transplanted in the standard (myeloablative) conditioning regimen up to age 55 to 60 years. The outcome after transplantation for those with indolent disease is superior to that in patients with more aggressive MDS. Recent data suggest that lower risk paitents (according to the WHO or WPSS) do very well with allogeneic transplanation, whereas those with 5% to 20% marrow blasts have only a 25% to 28% 5-year overall survival.

Because of the possibility of diminishing overall life expectancy resulting from treatment-related mortality in those with good prognosis, it is recommended that allogeneic transplantation be used in low and intermediate-1 IPSS patients only after disease progression, whereas patients with more aggressive histology/prognosis should be transplanted immediately on recognition that a donor exists.

Treatment-related mortality difference between matched-sibling transplantation and matched unrelated donor transplantation is very small, as a result there is no distinction about whether there is a family donor or a unrelated donor.

For patients between 55 and 70 to 75 years of age, it is reasonable to consider a reduced-intensity conditioning (RIC) regimen. It is clear that treatment-related mortality associated with RIC is no higher than that seen with full transplantations in younger patients. However, the major problem of this approach is that we lack of long-term data with regard to disease relapse.

Another problem for transplantation, particularly for RIC, is the excess marrow myeloblasts or the relevance of disease control. It is clear that in AML patients fewer marrow blasts at the time of transplantation portend for a better outcome than if the transplantation is done in the presence of more fulminant disease. But in MDS patients the indication of chemoresponsivity or the value of pretransplantation cytoreduction is unclear. Nonetheless, the presence of more than 5% to 10% blasts in the marrow of an MDS patient probably makes transplantation, particularly with RIC, less likely to succeed. So it is therefore reasonable to administer one or 2 cycles of “MDS-induction therapy” with a DNA-hypomethylating agent in an attempt to “perform an in vivo purge” of the marrow blasts before the allogeneic procedure.

Lenalidomide

For MDS patients with “5q-” syndrome, or with 5q- cytogenetic abnormality alone without the syndrome, or 5q- with other cytogenetic abnormalities, an effective therapy has emerged. Lenalidomide produces a 67% rate of transfusion independence and major increases in the hemoglobin. Although the FDA-approved label for lenalidomide calls for dose modification if myelosuppression is noted, recent data suggest that a more aggressive dosing scheme might be considered if optimal support can be provided. The median time to response is 4.4 weeks; the median duration of the response has not yet been reached. However, the clinical trial detailing this impressive responsive rate was restricted to those with low-risk and IPSS-1 disease, platelet counts greater than 50,000, and neutrophil counts greater than 500.

But with the rationale of lenalidomide implying that major disease-modifying activity is possible because of likelihood of elimination of the karyotypically abnormal clone, lenalidomide dose appear to be a major advance for patients with 5q- chromosome abnormalities and should be used as initial therapy in such patients who require treatment.

Immunosuppressive Therapy

The patient subgroup who might benefit from immunosuppressive is difficult to define. The rationale of immunosuppressive therapy is that immune-mediated suppression of normal stem cell function, analogous to the situation in aplastic anemia, has been postulated to account for cytopenias in some MDS patients. Selected patients treated with either cyclosporine A or an antihympcyte-globulin (ATG) based regimen can experience improvements in cytopenia in about one-third to one-half of the cases. Patients who are HLA D15 positive, who tend to be younger, or who have lower platelet count irrespective of marrow cellularity are more likely to respond to such immunosuppressive manipulations. Conversely, another study suggests that hypocellularity and low IPSS score are predictors of response to immunosuppressive therapy. Of note, studies to define the optimal patients in whom such therapy is appropriate remain to be developed.

Table 4. Proposed Modified International WorkingGroup (IWG) Response Criteria for MDS

Table 5. Proposed Modified International WorkingGroup (IWG) Response Criteria for Hematologic Improvement

Cheson et al. Blood. 2006;108:419‐425.

Cheson et al. Blood. 2000;96:3671‐3674. (The old IWG response criteria)

Patients who are non 5q- and ineligible for immunosuppressive therapy and transplantation

Lenalidomide. A trial including 214 patients with non 5q- MDS were treated with lenalidomide at a starting dose of 10 mg daily (either continuously or on a cycle of 21 days on, 7 days off) were recently published. A total of 26% of these patients experienced a reduction in their transfusional needs, which is roughly comparable with what is often obtained with erythropoietin or DNA-hypomethylating agents. The median time to response was 4 weeks and the duration of response was 7 months.

However, the eligibility for this trial required low or intermediate-1 IPSS risk MDS and excluded patients with secondary MDS or those who platelet counts were less than 50,000/μL or whose neutrophil counts were less than 1000/μL.

DNA-hypomethylating agent. Clinically, those with MDS subtypes with excessive numbers of marrow myeloblasts resemble the situation in high-risk (older patient or adverse chromosome prognosis) AML. The class of drugs most useful in MDS and applicable to all subtypes are the DNA-hypomethylating agents 5-azacitidine and decitabine.

Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.

Ont clinical trial showed that an early crossover design dampened any potential survival benefit attributable to azacitidine. However, the results demonstrated a delay in time to transformation to AML in those initially randomized to the study drug. There was a much higher response rate in the experimental  arm, and an ancillary quality of life study proved that patients randomized to azacitidine fared better.

We administer 4 cycles at 75 mg/m2 subcutaneously for 7 days every 28 days, rarely make dose adjustments, and do a bone marrow after cycle 4 to determine whether additional cycles are indicated. However, for many, the decision to continue or not is relatively difficult.