Practical Applications of the IPSS-R in MDS

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Rationale for risk stratification in myelodysplastic syndromes

Due to the heterogeneity of MDS, survival of MDS patients varies between a few months and decades. Precise diagnosis and accurate risk assessment are important for the management of MDS patients. Establishing the prognosis for patients with MDS is important because it helps them understand the severity of their disease and sets expectations for their future.1 For physicians, an accurate estimate of prognosis drives decisions about the timing and choice of therapeutic options to consider.1,2

Several prognostic systems have been developed to predict disease progression and prognosis in MDS; and until recently, the International Prognostic Scoring System (IPSS) served as the gold standard for predicting prognosis. Despite the utility of the IPSS, heterogeneity within some of the risk categories remained. Greater understanding of the cytogenetics of MDS as well as the disease pathophysiology have led to further analyses and a Revised IPSS (IPSS-R) was published in 2012.3

The Revised International Prognostic Scoring System (IPSS-R)

Overview of the IPSS-R

The IPSS-R arose from the analysis of 7,012 patients with primary, untreated MDS from 11 countries.2 Using multivariate modeling, prognostic risk was determined for overall survival as well as time to AML. Based on these analyses, several new prognostic risk factors were identified, while others were refined. Five main features were identified as predictors of prognosis and 5 prognostic categories were identified. The resulting model is shown in Table 1.

Table 1. Definition of the Revised International Prognostic Scoring System (IPSS-R)

Score

0

0.5

1

1.5

2

3

4

Cytogenetic risk group

Very good

Good

Intermediate

Poor

Very Poor

Bone marrow blasts

<2%

>2% to <5%

5% to 10%

>10%

Hemoglobin g/dL

>10

8 to <10

<8

Platelets/mcL

>100

50 to <100

<50

Granulocytes/mcL

>800

<0.8

SOURCE: Greenberg, et al.3

One of the most important changes to the IPSS was the refinement of the cytogenetics. In the IPSS, 6 separate cytogenetic abnormalities were included in the model. In contrast, the IPSS-R includes 16 individual abnormalities (Table 2). Further, the cytogenetic risk groups were expanded from 3 groups to 5 groups (Table 2). Importantly, the cytogenetic analyses, specifically standard karyotyping (at least 20 metaphases), should be performed on bone marrow biopsy samples. Fluorescence in situ hybridization (FISH) is inadequate to accurately characterize patients.

Table 2. Cytogenetic risk groups

Cytogenetic risk group

Cytogenetic abnormalities

Median survival, years

Very good

−Y, del(11q)

5.4

Good

Normal, del(5q), del(12p), del(20q), double including del(5q)

4.8

Intermediate

del(7q), +8, +19, i(17q), any other single or double independent clones

2.7

Poor

−7, inv(3)/t(3q)/del(3q), double including −7/del(7q), complex: 3 abnormalities

1.5

Very poor

Complex: >3 abnormalities

0.7

SOURCE: Greenberg, et al.3

Unlike the IPSS, analysis of the marrow blasts using clinically relevant cutpoints showed striking differences for both survival and AML evolution for patients with blasts 0% to ≤2% (lower risk) compared with blasts >2% to <5% (Figure 1).3 Review of the data indicated that baseline depth of cytopenias were statistically and clinically important. Thus, the depth of cytopenias and not just the presence of cytopenias is a key determinant of prognosis in the IPSS-R.

Figure 1. Marrow blast subgroups, impact on overall survival (a) and (b) time to AML


a.

b.

SOURCE: Greenberg, et al.3

Outcomes for patients in each prognostic risk group are shown in Table 3 and Figure 2.

Table 3. Prognostic risk groups

Prognostic risk group

Risk score

Mortality rate

Median survival, years*

Median time to 25% AML evolution*

Very good

<1.5

27%

8.8

Not reached

Good

>1.5 to 3

40%

5.3

10.8

Intermediate

>3 to 4.5

55%

3.0

3.2

Poor

>4.5 to 6

71%

1.6

1.4

Very poor

>6

86%

0.8

0.73

* P <.001
SOURCE: Greenberg, et al.3

Figure 2. Outcomes for patients in each prognostic risk for survival (a) and AML evolution (b)

a.

b.

SOURCE: Greenberg, et al.3

The impact of age was a major prognostic parameter for overall survival, but not for AML evolution.3 In the IPSS-R prognostic model, the data were shown for age 70 years, which was the near median age of the patient cohort. Greenberg and colleagues3 provide a formula, which permits statistical adjustment of survival prognosis for patients of all ages.

Adjustment of IPSS-R for age:
(years % 70) x [0.05 % (IPSS-R risk score x 0.005)]

Additional significant differentiating features for predicting survival were found, although their impact on prognostic score was relatively low compared with the 5 major features and age. These included performance score, serum ferritin, lactate dehydrogenase, and possibly b2-microglobulin.3

To summarize, the refinements of the IPSS-R beyond the IPSS include:

  1. New marrow blast categories
    • ≤2%, >2% to <5%, 5% to 10%, >10% to 30%
  2. Refined cytogenetic abnormalities and risk groups
    • 16 (vs 6) specific abnormalities, 5 (vs 3) subgroups
  3. Evaluation of depth of cytopenias
    • Clinically and statistically relevant cutpoints used
  4. Inclusion of differentiating features
    • Age, performance status, serum ferritin, lactate dehydrogenase; β2-microglobulin
  5. Prognostic model with 5 (vs 4) risk categories
    • Improved predictive power

An easy to use app for iOS and Android devices can be found at
http://www.mds-foundation.org/additional-tools/

Validation of the IPSS-R

Although the IPSS-R was developed using a robust cohort of MDS patients, it is important that the scoring system is applicable for all primary MDS patients. In this regard, numerous studies have investigated and validated the IPSS-R for patients who have not received treatment4-9 and for those who have received active treatment.10-14

Li and colleagues demonstrated that stratification of patients according to IPSS-R categories could be used to predict the clinical and cytogenetic response to decitabine treatment.11 In the study, 87 patients who received decitabine treatment were divided into 3 groups (very good plus good, intermediate, and poor plus very poor) according to the IPSS-R. The results showed that the patients carrying poor or very poor karyotypes showed statistically significantly complete responses, overall cytogenetic response, and cytogenic complete responses when compared with those with intermediate cytogenetic risk. The study results suggested that IPSS-R cytogenetic risk stratification could predict decitabine response.11 Similar findings were reported by Mishra and colleagues11 who found that patients in the high and very high risk groups derived the greatest benefit in overall survival when treated with hypomethylating agents or allogeneic stem cell transplant.

Selecting treatment based on IPSS-R risk group

The National Comprehensive Cancer Network guidelines for MDS V1.2016 recommend stratifying patients according to IPSS or IPSS-R (preferred) risk categories in the initial planning of therapeutic options as they provide for a risk-based patient evaluation (category 2A).2 Other factors such as the patient’s age, performance status, and the presence of comorbidities are additional critical determinants, since they have a major influence on the patient’s ability to tolerate certain intensive treatments.2

For patients in IPSS-R risk groups of very low, low, and intermediate, the NCCN guidelines recommend management of symptoms with the exception of patients who harbor the del(5q) abnormality. Patients with del(5q) and symptomatic anemia should receive lenalidomide at 10 mg once daily for 21 days, every 28 days.2 The guidelines also suggest that treatment response be assessed 2 to 4 months after initiation. Lenalidomide should not be administered to patients with a clinically significant decrease in neutrophil or platelet counts. An alternative for these patients may include an initial trial of erythropoiesis-stimulating agents (ESAs).

Patients without the del(5q) abnormality with symptomatic anemia are categorized according to serum erythropoietin (sEpo) levels and treatment is described in Table 4. Patients should be carefully monitored for disease progression regardless of treatment strategy. Furthermore, treatment selection should be guided by patient preferences with regard to regimen and timing of initiation.2

Table 4. Treatment of IPSS-R very low, low, or intermediate patients without del(5q) cytogenetic abnormality

sEpo ≤500 mU/mL

sEpo >500 mU/mL

First line: ESAs with/without granulocyte colony stimulating factor

First line: ATG or cyclosporine

ESA nonresponders: ATG or cyclosporine

ATG/cyclosporine nonresponders: hypomethylating agent, lenalidomide, clinical trial

ATG/cyclosporine nonresponders: lenalidomide, hypomethylating agents, clinical trial

Hypomethylating agent, lenalidomide nonresponders: clinical trial, allogeneic stem cell transplant

SOURCE: NCCN Guidelines 20162

Patients in the intermediate IPSS-R risk group can be treated as very low/low risk or as high/very high risk depending on additional prognostic factors such as age, performance status, serum ferritin levels, and serum lactate dehydrogenase levels.2

For patients with IPSS-R intermediate, high, or very high risk, treatment is stratified according the patients’ ability to tolerate intensive therapy. Determination of eligibility hinges on patient age, performance status, absence of major comorbidities, psychosocial status, patient preference, and availability of a suitable donor and caregiver.2 Intensive therapy options include allogeneic stem cell transplantation (Table 5) and intensive chemotherapy.

Patients eligible for intensive therapy for which there is no available donor should be considered for azacitidine or decitabine, intensive chemotherapy, or clinical trial. Numerous intensive chemotherapy regimens have been investigated with no clear choice identified. NCCN guidelines recommend a clinical trial or standard induction regimens if a clinical trial is not available or if high-dose chemotherapy is being used as a bridge to allogeneic stem cell transplant.2

Table 5. Allogeneic stem cell transplantation recommendations for patients with IPSS-R intermediate, high, or very high-risk prognosis

Donor:

  • HLA-matched sibling.
  • HLA-matched unrelated.

Conditioning regimen:

  • High-dose conditioning recommended for younger patients.
  • Reduced intensity conditioning recommended for older individuals.
  • If blast count is high, consider debulking therapy.

Timing:

  • High-risk patients ≤60 years best transplanted (HLA-matched sibling) shortly after diagnosis.
  • Intermediate-risk patients – decision should be made on an individual basis.
  • Low-risk patients best transplanted after disease progression.

SOURCE: NCCN Guidelines 20162

Nonintensive therapy includes azacitidine (preferred) or decitabine or clinical trial. Adequate supportive care should be maintained for patients with adverse clinical features or disease progression despite therapy and for whom reasonable specific anti-tumor therapy is not available.2

Practical tips for communicating prognosis to patients

No studies have been conducted to specifically evaluate an intervention to facilitate communication of prognosis. However, several general intervention studies have reported results relevant to the communication of prognosis.

Numerous challenges to providing prognostic and subsequent treatment information to patients and their caregivers exist. One difficult negotiation for oncologists in communicating prognosis is meeting the needs of the caregivers while also respecting those of the patient.15 Studies have provided conflicting results as to the best approach, and at this time it appears that physicians believe that prioritizing the needs of the patients supersede those of the family members.15,16

Another issue is ensuring patients have a clear understanding of their prognosis and its implications for their treatment options. A common finding across studies is that many patients report either not being told their prognosis or are found to misunderstand the status of their disease, the aim of their treatment, and their prognosis.17,18 Patients often overestimate their chances of cure and expected survival.19-24

Contrary to their needs, cancer patients do not always receive sufficient information from health care providers.25-28 The 2013 Institute of Medicine Report on Delivering High-quality Cancer Care: Charting a New Course for a System in Crisis stresses the continued need for comprehensive patient-centered care.29 The report also documents patients’ desire to be informed about their disease and treatment. The report also recommends that the cancer care team should communicate and personalize this information for their patients, and collaborate with their patients to develop care plans.29

Importantly, patients cannot express informed preferences unless they are given sufficient and appropriate information, including detailed explanations of their condition and the likely outcomes with and without treatment. They also need to be encouraged to express their concerns, beliefs, values, and preferences.30 Decision aids are intended to help patients and caregivers participate in decisions that involve weighing the benefits and harms of treatment options. Results of studies show that the use of decision aids has led to increased patient understanding of treatment options, which includes information about prognosis with and without treatment.31 A Cochrane database systematic review showed that decision aids can improve knowledge and they have a positive effect on patient-health care provider communication.32 Furthermore, exposure to decision aids allowed patients to make informed choices about their treatment including selecting more conservative forms of treatment.33 Other studies have shown that patients given a question prompt list asked significantly more questions about prognosis.34-36 In another study, endorsement of the question prompt list by the oncologist significantly increased discussion about prognosis.34

Further, considerable literature exists regarding different prognostic information needs of patients of different cultures. Thus, cultural competency is an important factor when communicating prognosis and treatment options to patients from different ethnic backgrounds.

Based on all evidence currently available, the best practices for communicating prognosis to patients with cancer are shown in Table 6.

Table 6. Practical tips for communicating prognosis to patients

Prior to discussing prognosis

  1. Ensure that the discussion will take place in privacy.
  2. Ensure as much as possible that there will be no interruptions (eg, switch off mobile phones and pagers; inform staff).
  3. Check first if a patient wants to be given prognostic information.
  4. Check if the patient would like to have a friend or relative present.
  5. Check if the patient would like another medical person present (if applicable).
  6. Explore and negotiate with the patient the type (eg, staging details; the chances of being cured; short and long-term side-effects of treatment; survival estimates) and format (eg, words, numbers, graphs) of prognostic information desired and adhere to these preferences.

When discussing prognosis

  1. Adopt an honest and straightforward yet sensitive approach.
  2. Encourage a collaborative relationship with the patient (eg, provide opportunity to ask questions).
  3. Use the most up-to-date information, and if desired, explain its source.
  4. Preface any statement of prognostic estimates with the limitations of prognostic formulations.
  5. If giving a time frame, emphasize a range and not specific endpoints.
  6. Use mixed framing, ie, give the chances of cure first then chances of relapse.
  7. Present information in a variety of ways (eg, words, graphs, statistics).
  8. Present absolute risks with and without treatment.
  9. Broaden discussion of the prognosis to include effect of the cancer on the individual’s lifestyle.
  10. Emphasize hope–giving aspects of the information, eg, extraordinary survivors.
  11. Repeat negotiation of information preferences and needs over time.
  12. Be aware that individual patient needs for prognostic information may change over time.

Following prognostic discussion

  1. Summarize the main points.
  2. Check that the patient has understood.
  3. Check the patient’s emotional reaction to the information.
  4. Inform the patient of available support.
  5. Organize a review appointment.
  6. Inform the patient of your availability and contact details in case of further questions.

Particular patient needs

  1. Different cultures: Exercise caution with information provision as the patient may come from cultures where avoidance or paternalism is the norm, and/or where family systems differ from the Western model. It may be necessary to explore the needs of patients and family members separately for information about prognosis, as these may differ.
  2. Anxious patients: May want less information.
  3. Depressed patients: May be more likely to want information about survival estimates.
  4. Age differences: Younger patients may want more information and older patients less.
  5. Gender: Female patients may want more information.
  6. Expected survival: Those with a worse prognosis may be less likely to want prognostic information.
  7. Education level: Those with less education may require more assistance to understand prognostic information.

SOURCE: National Breast Cancer Centre37

Conclusions

A growing body of evidence has established that the IPSS-R is a valid and effective prognostic tool for patients with primary MDS. Data suggest that the IPSS-R is equally effective in assessing prognosis in newly diagnosed as well as treated patients with MDS. Incorporation of the IPSS-R into routine clinical practice is now a viable and preferred option and its use constitutes a necessary step as part of treatment selection and patient management.

References

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