A 70 year old male (Mr. G) presented to ER with complaints of giddiness for 3 days, shortness of breath(grade 2 to 3) for 3 days, fever with chills for 1 day, weight loss of 2 to 3 kgs in 6 months, lower back pain for 6 months, right eye swelling with pus discharge. Patient was evaluated at an hospital elsewhere and found to have low haemoglobin (4.3 g%) and WBC(2000/cu.mm). Patient came to our Hospital for further management. Patient was a known case of benign prostatic hyperplasia, left inguinoscrotal hernia with bowel and omentum as content. He did not have any known drug allergy. Patient had a history of consumption of native medication for various illnesses in the past. He was vaccinated with 2 doses of covishield.
On arrival at ER, he was febrile (100.4 F), pale. BP-120/70 mmHg, pulse rate-111/min, respiratory rate- 22/min, SpO2- 99% in room air, CBG-226 mg/dl. Systemic examination showed no gross abnormality except for left iliac fossa swelling extending into the scrotum. There was no lymphadenopathy or hepatosplenomegaly. Local examination of the right eye revealed swelling, redness around the inner canthus of the eye associated with tenderness and pus discharge. Basic blood investigations done showed bicytopenia with haemoglobin – 4.4 g%, hematocrit-13.3% , MCV- 87 fL, WBC- 1400/cu.mm(polymorphs-81.9, lymphocytes- 13.6), Platelet- 1,25,000, CRP- 124, S. procalcitonin- 0.44, S. Albumin- 3.11, PT INR- 1.88, Sodium- 126.9. Anaemia work up done revealed S.Ferritin – 418, S. Iron-33, Reticulocyte count- 0.9%, LDH- 455. Coomb’s direct and Coomb’s indirect were negative.
Vitamin B12 and folic acid levels were normal. Peripheral smear showed normocytic normochromic anemia.
Fever profile was done to rule out tropical infections. Dengue IgM, Dengue NS1 Ag, MPQBC ( Malarial parasite quantitative Buffy coat) were negative. In view of Shortness of breath, COVID RTPCR was done which turned out to be negative. ECHO was normal (LVEF- 60%). CT abdomen done revealed large left inguinoscrotal hernia with bowel and omentum as content, bilateral mild perinephric fat stranding, over distended urinary bladder with mild bladder wall thickening and enlarged prostate, Liver and spleen size were within normal limits. CT chest done showed Ill-defined ground glass opacities in the lateral basal segment of bilateral lower lobes, predominantly in the subpleural region – indicating Atypical pneumonia. This patient had multiple infections- Right eye dacryocystitis, pyelonephritis, cystitis, atypical pneumonia with anemia and leucopenia. Patient had multiple fever spikes during first five days of admission. Urine culture and blood culture were done. He was started on Meropenen which was subsequently changed to Piperacillin Tazobactam.
Ophthalmologist opinion was sought in view of dacryocystitis who advised Moxifloxacin eye drops. Swelling, redness and pus discharge decreased during the course of hospital stay. USG abdomen done to assess prostate size revealed a volume of 65 ml. Patient had urinary retention because of BPH and was catheterised with a Foleys catheter. He was on continuous bladder drainage throughout hospital stay. Trial of self-void of urine was tried twice during hospital stay but patient was not able to initiate micturition. Urine culture grew Pseudomonas aeroginosa. Patient was transfused with 3 units of packed red blood cells. Patient tolerated transfusion well. Hematologist opinion was sought and bone marrow biopsy with aspiration was advised. After informed consent, bone marrow biopsy, bone marrow aspirate, GeneXpert, Culture for TB, Karyotyping were done.
Bone marrow aspirate showed moderately hypercellular fragments with increased blasts (11%), dysgranulopoiesis, dysmegakaryopoiesis(MDS IB-2). Bone marrow biopsy showed hypercellular marrow with granulocytic hyperplasia, dysgranulopoiesis and increase in immature cells and megakaryopoiesis. Bone marrow Karyotyping showed 45, XY,-7,-20. FISH panel for MDS showed Monosomy 7, del 20q. Revised International Prognositc Scoring n System (IPSS-R) = 7.5 points classifies him as very high risk with median survival = 0.8 years. A diagnosis of Myelodysplastic syndrome was made. At the time of diagnosis, WHO 2015 classification of MDS was in use and he was designated to have MDS EB2 ( Myelodysplastic syndrome with excess blasts). A new classification of MDS was adopted by WHO in 2022 and based on that, he was categorised as MDS/AML with myelodysplasia related changes.
After explaining the nature of the disease, prognosis, treatment protocol and side effects to the patient and his attenders, he was started on 1st cycle (18 to 24 August 2022) of hypomethylating agent (Inj. Azacytidine at a dose of 75 mg/ m2 of body surface once daily for 7 days). He had fever spikes on day 2, 3, 4 of chemotherapy which subsided with symptomatic management. Renal function and liver function remained normal throughout hospital stay and during chemotherapy. Patient was discharged after 1st cycle of chemotherapy. CBC at the end of 1st cycle revealed hemoglobin- 8.8, WBC- 3,200, Platelet- 2,37,000. Subsequently, he underwent 3 more cycles of chemotherapy in the next 3 months. He underwent laparoscopic mesh repair of left inguinoscrotal hernia after completion of 4 cycles of chemotherapy. He is currently under follow up and is due for his next cycle of chemotherapy.
Myelodysplastic syndrome (MDS) is caused due to progressive accumulation of mutations in hematopoietic stem cells of bone marrow in aged population characterized by ineffective erythropoiesis and peripheral cytopenia. It is a syndrome seen mostly in elderly and rarely in children. Mutations could be due to radiation exposure, chemical exposure such as benzene. Our patient (Mr. G) had exposure to native medicines in the past and his karyotype also shows abnormality of chromosome 7 (monosomy 7). MDS can occur secondary to usage of chemotherapeutic agents like busulfan, procarbazine, irinotecan, topotecan, teniposide. It is termed as t-MDS (therapy related MDS). MDS can rarely occur secondary to Fanconi anaemia. MonoMac syndrome characterized by decreased monocytes, NK cells and B cells(due to GATA2 mutation) may progress to MDS. Germline RUNX1 mutation which manifest initially as moderate thrombocytopenia can progress to MDS. MDS is characterized by defective differentiation, disordered cell proliferation, bone marrow suppression and rarely, progression to leukemia. Telomere attrition caused by age predisposes the patient multiple genetic mutations and chromosomal abnormalities. Aneuploidy is more common than translocation. Partial or complete loss of 5,7,20 chromosomes are seen. Mutations seen in MDS overlap with AML and Sideroblastic anaemia.SF3B1 which causes a spliceosomal defect is also seen in Sideroblastic Anemia. EZH2, RUNX1, TP53 and ASXL1 mutations are also seen and have good prognosis. 5q deletion seen in MDS is associated with aplastic anemia.
2015 WHO classification of MDS is based on lineage of cells involved, percentage of ringed sideroblasts, myeloblasts in bone marrow, myeloblasts in peripheral smear, presence of Auer rods. > 15% ringed sideroblasts is designated as MDS with ringed sideroblasts.> 5% myeloblasts in bone marrow or >1% myeloblasts in peripheral smear is termed as MDS with excess blasts. Presence of Auer rods or BM blasts > 20% shows progression to AML.
New classification of MDS adopted by WHO in 2022 brings cytogenetic abnormalities like TP53 alterations, SF3B1 mutations, isolated 5q deletions and 7 monosomy into picture. Irrespective of the % of blasts in bone marrow or peripheral smear, the presence of any of the above mentioned cytogenetic abnormalities, categorises patients under MDS/AML with myelodysplasia.
Symptoms of anemia are the most common presenting complaints. Some patients are incidentally found to have anemia which when worked upon reveals MDS.
Smear studies reveal anemia with bicytopenia or pancytopenia. Macrocytosis due to BM failure is seen. Megakaryocytes without granules, hypogranulated – hyposegmented nucleus- non functional neutrophils are seen. Myeloblasts which correlate with BM blasts are seen. % of myeloblasts correlates with prognosis. Leucopenia is seen.
Bone marrow studies reveal hypercellular marrow with signs of dyserythropoiesis( megaloblastic nuclei, defective hemoglobin), hyposegmented and hypogranulated neutrophil, megakaryocytes with disorganised nuclei.
Acute viral infection, drug toxicity, Vitamin B9 and B12 deficiency, Copper deficiency can cause cytopenias with bone marrow dysplasia and should be ruled out.
Prognosis is based on % of myeloblasts, depth of cytopenia, presence of certain mutations, cytogenetic abnormalities as put forward by IPSS-R(International prognostic scoring system – revised) Hypomethylating agents and pyrimidine analogues such as Azacytidine, decitabine act as epigenetic modulators and helps in differentiation of blood cells in bone marrow. These agents can themselves cause myelosuppression as a side effect. Lenalidomide can be used in 5q syndrome but it can also cause myelosuppression. Lenalidomide increases risk of deep vein thrombosis and pulmonary embolism. Immunosuppression with Cyclosporine, Alemtuzumab(Anti CD 52 monoclonal antibody) is useful in young MDS with low risk IPSS-R. Erythropoietin with Granulocyte- colony stimulating factor can be used in low risk IPSS-R. Venetoclax, an apoptosis inhibitor (bcl2 protein inhibitor) can be used.
Bone marrow transplantation is the definitive cure for MDS. But, patients with high risk (IPSS-R) who actually require BM transplant are usually very old and may develop transplant related issues. Patients with low risk IPSS-R can tolerate stem cell transplant much better than those with high risk IPSS-R.
Dr Azharuddin M DNB Resident (General Medicine) Kauvery Hospital Chennai
