Sokal Index for CML

Why use it

The Sokal Index provides the foundational risk stratification framework for newly diagnosed CML, guiding the selection of first-line TKI therapy: High-risk Sokal patients may benefit from a second-generation TKI (dasatinib, nilotinib, or bosutinib) rather than imatinib as first-line therapy, given their lower response rates to imatinib and higher risk of progression. ELN 2020 guidelines incorporate the Sokal (or ELTS) score for initial risk stratification and as a baseline variable for monitoring response milestones. The score is also required for entry into most CML clinical trials and is used to adjust expected treatment milestones.

About

The Sokal Index is the original and most widely validated prognostic scoring system for newly diagnosed chronic myeloid leukemia (CML) in chronic phase, developed by Sokal and colleagues and published in Blood in 1984. It was derived from a cohort of 813 patients with CML treated in the pre-tyrosine kinase inhibitor (pre-TKI) era, primarily with busulfan or hydroxyurea. The Sokal formula uses four continuous clinical variables measured at diagnosis: patient age (years), spleen size below the costal margin (cm, measured by palpation), platelet count (×10⁹/L), and peripheral blood blast percentage. These four variables are combined in an exponential formula to generate a continuous risk score, which is then classified into three prognostic groups — Low (< 0.8), Intermediate (0.8–1.2), and High (> 1.2). Although derived in the pre-TKI era, the Sokal Index retains significant prognostic relevance in the imatinib era: patients classified as High-risk by Sokal have consistently lower rates of complete cytogenetic response (CCyR), major molecular response (MMR, BCR-ABL1IS ≤ 0.1%), and deep molecular response (DMR, MR4.5) to first-generation TKI therapy, and higher rates of transformation to accelerated or blast phase. An alternative scoring system — the EURO (Hasford) Score — was published in 1998 and incorporates basophil and eosinophil percentages, and may provide superior discrimination in some cohorts. The more recently developed EUTOS Long-Term Survival Score (ELTS Score, 2020) was specifically developed in TKI-treated patients and may better predict outcomes in contemporary practice.

When to use

• Newly diagnosed CML in chronic phase before initiation of TKI therapy
• Use values measured at diagnosis — before any cytoreductive therapy is initiated (including hydroxyurea)
• Spleen size must be measured by clinical palpation (cm below costal margin), not by imaging
• Platelet count is the absolute count from the CBC at diagnosis
• Blast percentage is from the peripheral blood differential count at diagnosis
• NOT validated for accelerated phase or blast crisis CML at presentation
• NOT validated for patients who have already started TKI therapy
• The ELTS Score (2020) should be considered as a complementary or preferred tool for predicting CML-specific mortality in TKI-treated patients — Sokal retains relevance for historical comparison and trial entry criteria

Formula

Pearls & pitfalls

• Spleen size in the Sokal formula is the distance of the inferior splenic edge BELOW the left costal margin in centimeters, measured by clinical palpation in the supine position — NOT by CT or ultrasound. A non-palpable spleen = 0 cm.
• The Sokal formula uses the EXPONENTIAL function: Score = exp[0.0116(age − 43.4) + 0.0345(spleen − 7.51) + 0.188((platelets/700)² − 0.563) + 0.0887(blasts − 2.10)]. Even small changes in input values can alter the score.
• The Sokal Index was derived from pre-TKI patients and correlates better with IFN-α era outcomes than with TKI-era outcomes. The ELTS Score (Pfirrmann et al. 2016, updated 2020) was designed specifically for TKI-treated patients and is now preferred by ELN 2020 for predicting CML-specific mortality.
• Despite its pre-TKI derivation, Sokal retains predictive value in the imatinib era: IRIS trial data showed High-Sokal patients had significantly lower CCyR rates (54% vs 76%) and more frequent failure events compared to Low-risk patients.
• Second-generation TKIs (dasatinib, nilotinib, bosutinib) substantially overcome the prognostic disadvantage of high Sokal score — in the DASISION, ENESTnd, and BFORE trials, High-Sokal patients receiving second-generation TKI achieved outcomes similar to Low-Sokal imatinib patients.
• Sokal score does NOT predict treatment-free remission (TFR) eligibility — the ability to attempt TKI discontinuation (TFR attempt) is based on the depth and duration of molecular response (sustained MR4.5), not the initial Sokal score.
• The EURO (Hasford) Score (1998) incorporates basophil and eosinophil percentages and may stratify intermediate-risk patients better than Sokal in some cohorts. If both are calculated, discordant classifications occur in approximately 15–20% of patients.
• Thrombocytosis (platelets > 700 × 10⁹/L) contributes positively to the Sokal score — very high platelet counts (> 1000 × 10⁹/L) may significantly elevate the score even in younger patients with modest splenomegaly.
• ABCB1/MDR1 polymorphisms and OCT1 expression (imatinib transporter) also influence TKI response independently of Sokal score and should be considered in treatment optimization, particularly for borderline imatinib-versus-second-generation-TKI decisions.
• ABL1 kinase domain mutations at baseline (particularly T315I — the "gatekeeper" mutation) predict resistance to all first- and second-generation TKIs except ponatinib and asciminib. Baseline mutation screening is recommended when the presentation is atypical or when accelerated-phase features are present.

Next steps

Low Risk (Sokal < 0.8): First-line imatinib 400 mg/day is appropriate and achieves CCyR in >85% of patients. Monitor BCR-ABL1IS at 3, 6, 12, and 18 months. Milestone responses per ELN 2020: BCR-ABL1IS ≤ 10% at 3 months, ≤ 1% at 6 months, ≤ 0.1% (MMR) at 12 months. Consider second-generation TKI if milestones not met. Intermediate Risk (Sokal 0.8–1.2): First-line imatinib or second-generation TKI (dasatinib, nilotinib, bosutinib) are both reasonable. Second-generation TKI achieves faster and deeper molecular responses. Consider patient comorbidities and TKI toxicity profile in selection. High Risk (Sokal > 1.2): Second-generation TKI (dasatinib, nilotinib, or bosutinib) is preferred over imatinib as first-line therapy — higher rates of CCyR, MMR, and deep molecular response (MR4.5) compared to imatinib in high-risk patients. Early evaluation for clinical trial enrollment. Monitor response closely — consider escalation or switch early if first optimal milestone (BCR-ABL1IS ≤ 10% at 3 months) is not met. Regardless of Sokal score: Monitor BCR-ABL1IS by PCR every 3 months until MMR, then every 3–6 months. Perform ABL kinase domain mutation analysis at any sign of resistance or suboptimal response.

Evidence

Sokal JE, Cox EB, Baccarani M et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood. 1984;63(4):789-799. PMID:6584184. Derivation: n=813 patients (busulfan/hydroxyurea era). Hasford J et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa (EURO/Hasford Score). J Natl Cancer Inst. 1998;90(11):850-858. PMID:9625174. Pfirrmann M et al. The EUTOS Long-Term Survival (ELTS) score is superior to the Sokal score for predicting survival in CML. Leukemia. 2020;34(8):2138-2149. PMID:32034319. O'Brien SG et al. (IRIS Trial). Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase CML. N Engl J Med. 2003;348(11):994-1004. PMID:12637609.

References

1. Sokal JE, Cox EB, Baccarani M et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood. 1984;63(4):789-799. — link
2. Hasford J et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa (EURO Score). J Natl Cancer Inst. 1998;90(11):850-858. — link
3. Pfirrmann M et al. The EUTOS Long-Term Survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia. Leukemia. 2020;34(8):2138-2149. — link
4. Hochhaus A et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966-984. — link
5. O'Brien SG et al. (IRIS Trial). Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase CML. N Engl J Med. 2003;348(11):994-1004. — link