M B Agarwal
Myelodysplastic syndrome (MDS) is a disease of elderly, characterized by ineffective haematopoiesis leading to cytopenia and a high risk of progression to Acute Myeloid Leukaemia (AML). Diagnosis is based on morphological assessment of blood and marrow, karyotyping and mutational analysis. These tests are also of prognostic value allowing even targeted approach to some of the subtypes e.g. del(5q).
Patients are classified according to International Prognostic Scoring System (IPSS) and the revised version of IPSS (IPSS-R) in to lower-risk MDS (LR-MDS) and higher-risk MDS (HR-MDS).
Molecular techniques identify somatic mutations in almost every patient of MDS. These mutations are of help in diagnosing of some of the difficulty cases. These have prognostic significance as well e.g. RUNX1, ASXL1 and TP53 have a negative impact while TET2 is neutral and SF3B1 has better prognosis. del (5q) has good prognosis and targeted therapy with Lenalidomide. However, this does not apply if there is associated TP53 mutation (20% of cases). SF3B1 can be of diagnostic value for MDS – ring sideroblasts (MDS-RS). This has Luspatercept as an effective treatment. IDH1 and IDH2 mutations also have specific treatment in the form of inhibitors. Presence of TP53 mutation makes treatment with chemotherapy ineffective, however, demethylating agents are helpful and act as a bridge to transplant (in transplant eligible patients).
Treatment of Lower-risk MDS (LR-MDS): In LR-MDS, the therapeutic goal is to improve anaemia and keep patient transfusion free, thereby improving quality of life (QoL). Those with mild cytopenia and without symptoms can be kept under watchful observation. Symptomatic anaemia with del(5q) are best treated with Lenalidomide with 67% success. Others without del(5q) may also respond to Lenalidomide with 20% success.
Erythropoiesis stimulating agents (ESAs), both erythropoietin (EPO) & Darbepoetin (DAR) are effective as single agent for most LR-MDS with anaemia and without del(5q). This is specially so if patients S. EPO is below 200 U/l and transfusion requirement is <2 units every month. Weekly dose of EPO is 30,000-60,000 units while 3-weekly dose of DAR is 500 μg. Response should be assessed after a minimum of 8 weeks of therapy. Efficacy is seen in 30-70% of patients. Addition of G-CSF can help another 15-20% of cases.
Immunosuppressive agents e.g. Anti-Thymocyte Globulin (ATG) with or without Cyclosporin (CsA) is effective in 20-30% of LR-MDS patients. Response predictors include MDS with single lineage dysplasia (MDS-RA), absence of ring sideroblasts, hypoplastic marrow, younger patients (< 60 years), female gender, HLA-DR15, normal Karyotype or Trisomy 8 & presence of paroxysmal nocturnal haemoglobinuria (PNH) clone. Iron chelation using Deferasirox – the new film coated formulation is effective in controlling iron overload in transfusion dependent LR-MDS. This has been shown to extend life.
Luspatercept is a new treatment for anaemia in LR-MDS specially MDS-RARS and those with SF3B1 mutation. It is a specific activin receptor fusion protein acting as a ligand trap to neutralize regulators of late-stage erythropoiesis. It is effective in 60% of patients and almost 35% of them become transfusion independent. It is an injection given subcutaneous every 3 weeks. Imetelstat is a telomerase inhibitor which leads to improvement in haemoglobin in 40% of LR-MDS resistant to treatment discussed above. Lastly, those with neutropenia may be helped by G-CSF (without much worry about increase incidence of AML) while others with severe thrombocytopenia with TPO-RA e.g. Eltrombopag or Romiplostim.
Hypomethylating agents (HMAs), both Azacitidine and Decitabine are mostly use for HR-MDS but may be tried in LR-MDS with some response (20%). Allogenic stem cell transplantation (Allo-SCT) is also typically indicated for HR-MDS but may be used for LR-MDS with poor prognostic features e.g. TP53 mutation, severe cytopenia, failure of treatment mentioned above etc.
Treatment of Higher risk MDS (HR-MDS): Hypomethylating agents are the key for treatment of HR-MDS. These are the first line treatment for majority of them. Both have been shown to have survival benefit over conventional care regimens (CCR) with a median survival of 24 months. This survival advantage is irrespective of age, marrow blasts percentage and karyotyping. Response is delayed with a median time to response of 4 months. Hence, a minimum of 6 cycles of therapy must be given before considering patient to be resistant. Response is seen in 50% of patients but CR rates are low (15%). Presence of TET2 mutation and absence of ASXL1 mutation are predictive of better favourable response. If effective, treatment must be continued until disease progression, although, clinician do increase the interval between cycles to 6 weeks or so. Levofloxacin is routinely used in the first 6 cycles of therapy with HMAs, especially in those with profound neutropenia. Systemic prophylactic antifungals, however, are not recommended.
In HR-MDS with complex karyotype or TP53 mutation, there is a suggestion of more intensive 10-day regimen of decitabine (20 mg/m2/day) every 28 days.
HMAs have been used in combination with other drugs including vorinostat, entinostat, lenalidomide, thalidomide and gemtuzumab ozogamicin (GO) with promising results. There is data on newer HMAs, including guadecitabine. Oral formulation of Azacitidine and Decitabine have also been tried. There is good evidence that bcl2 inhibitor venetoclax is useful in elderly AML who are in eligible for IC. There are suggestions that Venetoclax with HMAs or cytosine arabinoside may be used with some success in HR-MDS.
Intensive chemotherapy (IC) using AML type of protocol has been challenged by the advent of HMAs. IC can induce complete response (CR) in 40% of patients, however, this is usually short lived. Moreover, those with unfavourable karyotype do poorly. This is a good option as a bridge to transplant for younger patients without unfavourable Karyotyping. CPX-351, a liposomal formulation of Cytarabine and Daunorubicin is a safer and effective option. IDH1 & IDH2 gene mutations are present in 5-10% of patients with MDS. IDH1 inhibitor (ivosidenib) & IDH2 inhibito (enasidenib) inhibitors are approved for AML. These drugs have also shown some efficacy in HR-MDS.
After HMA failure, currently, outcome of patients with HR-MDS is poor with median survival of 6 months unless they receive allo-SCT. Whenever feasible, allo-SCT, the only curable treatment for HR-MDS with long term disease – free survival of 50% should be offered to HR-MDS. However, this option is available to only 8% of patients.
Correspondence: Professor M B Agarwal, Head of the Department of Haematology, Bombay Hospital Institute of Medical Sciences, Mumbai, India. Email ID: [email protected]. Mobile: +91 9820024850.