Hematology: White blood cells disorders

prognosis of ALL:

the 5 years survival rate is 85%-90% with treatment

trearment of AML:

(Aim of treatment is to induce complete resmission, less than 5% blasts in the bone marrow, normal blood counts and clinical status) (Treatment phases: induction, consolidation and consolidation) -Cytosine arabinoside and daunorubicin -Idarubicin, mitoxantrone and etoposide are also used in various regimens

Complications of AML:

-anemia -infection -bleeding. -neutropenic enterocolitis, -disseminated intravascular coagulation (DIC), - hyperleukocytosis -tumor lysis syndrome

The most common leukemia of all leukemias:

CLL

FCR-regimen and BR-regimen for CLL:

(FCR-regimen): -Applied in patients in good general condition -Fludarabin -Cyclophosphamide -Rituximab (BR-regimen): -For patients with reduced general condition -Chloambucil -Bendamustine -Rituximab

Burkitt's lymphoma genetics:

-t(8;14), t(2;8), t(8;22) in Burkitt's lymphoma/ c-myc oncogene

List different malignant/potentially malignant monoclonal gammopathies:

(MGUS is premalignant) 1. Multiple myeloma (MM): a. Active (symptomatic) MM b. Smouldering (asymptomatic) SMM c. Plasma cell leukaemia d. Non-secretory MM (NSMM) 2. Plasmacytomas: a. Soliter bone-plasmocytoma b. Extramedullary plasmocytoma 3. Immunoglobulin deposition diseases a, Primary amyloidosis b. Systemic LC / HC deposition 4. Waldenström's macroglobulinemia: (lymphoplasmocytic lymphoma, IgM, organomegaly, hyperviscosity) 5. POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal paraprotein, skin changes 6. Heavy-chain disease (HCD) γ-HCD, α-HCD, μ-HCD 7. Malignant lymphoproliferative diseases, lymphomas (CLL, MZL etc.) 8. other malignancies (GI, lung, brest, etc.)

General treatment of ALL:

(Supportive treatment): -Anemia by red cell concentrate transfusions -Bleeding with platelet tranfusions -Infections with empiric antibiotics (Specific treatment): /Aggressive and it is intended to cure the disease /Kills the malignant cells (rapidly proliferating cells) /Has side effects e.g. hair loss, mouth sores, BM suppression, diarrhea /Has three phases: Remission induction, Remission consolidation, Remission maintenance

Clinical presentation of ALL:

(The most common clinical manifestations of ALL are bleeding, pallor, and infections. These symptoms develop abruptly within days or weeks and are due to the replacement of normal bone marrow cells by the malignant cells.) -Bleeding (purpura, echomyosis, epistaxis, gingival bleeding) -Anemia signs -Increased infections -bone pain and tenderness -hepatomegaly, splenomegaly -swelling of testicles -CNS involvement -signs related to hyperviscosity

Myeloma defining events:

(Treatment is started when there is): -Any CRAB criterion -Or any of 3 biomarkers: /more than 60% plasma cells in BM (or iFLC/uFLC more than 100) /More than one focal lesion on MRI greater than 5mm diameter (Patients w/out any CRAB or MDE: smouldering myeloma)

Other treatment options in CML:

-Bone Marrow Transplantation The allogeneic bone marrow transplantation (BMT) is the only proven cure for CML. Ideally, it should be offered to all the candidates if a matched donor is found, but the promising results of imatinib and related drugs have limited the BMT to individuals with poor prognosis and treatment resistance. -Interferon-alpha was previously the first-line drug to manage CML. Interferon-alpha is still given in accelerated phase/blast crisis in combination with imatinib and in the imatinib-resistant cases. -Hydroxyurea and busulfan are anticancer drugs that decrease the blood cell count for palliation without affecting the Philadelphia chromosome or progression to accelerated phase/blast crisis. -Splenectomy may be done for palliation in patients with late-stage CML complaining of pain and discomfort due to the enlarged spleen and splenic infarcts.

Epidemiology of AML:

-AML is more common in men than women and usually affects individuals above the age of 65 years.

Classifications of leukemias:

-Acute leukemias /Acute lymphoblastic leukemia (ALL) is ranked as the most common malignant disease in children. /Acute myeloid leukemia is also common among children. It is characterized by the replacement of the normal bone marrow cells with dysplastic hematopoietic cells. -Chronic leukemias /Chronic lymphocytic leukemia /Chronic myeloid leukemia

Different leukemias based on age groups:

-Age 40—60 years: myeloid leukemia (AML & CML) -Age 0 —14 years: acute lymphocytic leukemia -Age 60 years and older: chronic lymphocytic leukemia

factors determining the prognosis of ALL:

-Age: Children have a better prognosis than adults. -Gender: Boys usually have a poorer prognosis than girls. -WBC count: High WBC counts (>100,000/mcl) are associated with a poor prognosis. -CNS involvement: CNS involvement is more common in adults and in relapses, and results in a poor prognosis. -Chromosomal abnormalities: These are the most important prognostic predictors. -Philadelphia chromosome t(9;22): timely is traditionally regarded as a poor prognostic factor, but Food and Drug Administration-approved bcr-abl tyrosine kinase inhibitors (imatinib) are gradually changing this outlook.

List different components of the normal electrophoresis graph of the blood proteins:

-Albumin -α1: TBG, α1-antitripsin, AFP etc -α2: PTR, coeruloplasmin, -haptoglobin, EPO -β: CRP, fibrinogen, complement, clotting factors -γ: immungolobulins

general features of Acute promyelocytic leukemia (M3):

-Associated with cytoplasmic inclusions. -Most cells are abnormal promyelocytes, often containing many Auer rods per cell; -Patients are younger on average (median age 35—40 yr); -high incidence of DIC; -strongly associated with t(15;17).

Diagnostic tests for multiple myeloma:

-Blood: CBC, Serum total protein, albumin, immunoglobulins, SPEP, Immunofixaion, creatnin, creatinine clearance, calcium, LDL, Beta-2-microglobulin, sFLC -Urine: 24h urine: UPEP, Immunofixation, Bence-Jones -Bone marrow: Biopsy and aspiration (histology, immunohistochemistry, flowcytometry), genetic testing -Skeletal imaging: X-ray, MRI, whole body low-dose CT, PET-CT, PET-MRI

Major symptoms of multiple myeloma:

-Bone pain, pathological fractures -Fatigue and paleness -Weight loss -Paresthesias -Symptoms related to abnormal proteins -Symptoms related to renal impairment -Hypercalemia -Immune deficiency -Bleeding tendency -Spinal cord compression -Compression due to plasmacytoma

Diagnosis of ALL:

-CBC is the initial Test for ALL. It often shows anemia with normal or high MCV and thrombocytopenia. WBCs count varies from 1000mcl to 500 000 mcl, with increased circulatory blasts -Bone marrow study is the next step. It is hypercellular with increased leukemic blasts. The diagnosis of ALL is made by the presence of more than 20% blast cells. T-ALL and B-ALL are distinguished by histo-cytochemistry and flow cytometry -Cytogenetic and karyotyping further subdivide B cell ALL into many groups, depending on the presence of chromosomal abnormalities. -In T-ALL a chest X-ray may be done to show mediastinal masses

B cell markers in ALL:

-CD19 -CD10 -TdT

T cell markers in ALL:

-CD2 -CD5 -CD7 -TdT

Clinical symptoms of CLL:

-CLL, like a slowly progressing disease of elderly people, often is an incidental finding in the investigation of a leukocytosis at hand; thus, almost 50% of the patients are free of symptoms at the point of diagnosis. -Early signs are general symptoms like fatigue, tiredness and performance dip, as well as classical signs of b symptoms. They involve the triad of night sweats, fever of unknown origin (FUO) and unintended loss of weight. -In the further course, a majority of the patients develops an enlargement of lymph nodes, lymphadenopathy that typically has a dense consistency and is indolent; moreover, an enlarged spleen (splenomegaly) or liver (hepatomegaly) is found quite often. -CLL can also become apparent on the skin in the form of pruritus, chronic urticarial, mycosis and herpes zoster. -A common and dangerous complication is antibody deficiency syndrome. Clonal CLL-cells displace the functional B-cell population and increase the risk of infections this way significantly. A reduced amount of granulocytes (neutropenia) advantages of bacterial infections. This is a major cause of death of this type of leukemia. -Other complications are autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia and a secondary transition into a highly malignant lymphoma

Philadelphia can be present in:

-CML -ALL -AML

CRAB criteria for Multiple Myeloma

-Calcium elevation: serum calcium >11.5 mg/dL - 2,75 mmol/l -Renal insufficiency: serum creatinine >177 umol/l or 2 mg/dL or creatinin clearance <40 ml/min -Anemia -Bone disease: one or more lytic lesion.

Pathophysiology of CLL:

-Chronic lymphocytic leukemia is based on an uncontrolled proliferation of mature B-lymphocytes. Generally, this population of B-lymphocytes is monoclonal, which means that it is made up of identical copies of a single B-lymphocyte. -Moreover, in the case of CLL, all cells appear mature, small and in good order, but they do not fulfill an immunological function. If these B-cell lymphoma cells reach the peripheral blood, it is referred to as a leukemic washout. -If the clonal B-cells are, for example, limited to a lymph node area, it is referred to as small cell lymphocytic lymphoma if it is consisting of the same type of cells. -In the course of the disease, the proliferating population of lymphoma cells also further increases in the bone marrow and extrudes other cell types, which explains the lack of erythrocytes (anemia), thrombocytes (thrombocytopenia) and functioning B-lymphocytes (antibody deficiency syndrome).

Pathophysiology of CML:

-Chronic myelogenous leukemia is classically associated with the presence of an acquired genetic abnormality, BCR-ABL fusion gene. The BCR-ABL fusion gene has tyrosine kinase activity and is responsible for the uncontrolled proliferation of cells. -In 95% of cases, this BCR-ABL fusion gene is formed due to the translocation of the ABL gene from chromosome 9 to the BCR gene on chromosome 22, t(9;22). This newly formed chromosome 22 having the BCR-ABL fusion gene is called the "Philadelphia chromosome". -It should be remembered that the Philadelphia chromosome, though characteristically associated with CML, is not restricted to CML only. It is also present in acute lymphoblastic leukemia (ALL), and rarely in acute myeloblastic leukemia (AML)

Diagnosis of CML:

-Complete blood count (CBC) is the initial investigation. It shows an increase in the white blood cells, predominantly in the myeloid series. The WBC count ranges from 10,000-600,000/mcl. The cells are mildly left-side shifted with an increase in myelocytes, meta-myelocytes, and pre-myelocytes, but the blast cells are usually less than 10% unless the patient presents with accelerated or blast crisis. Basophils and eosinophils are also elevated. Hematocrit is usually normal with normal RBC morphology. Platelets are usually increased. -Karyotyping will reveal the presence of Philadelphia chromosome t(9;22). -The characteristic CBC findings with the presence of the Philadelphia chromosome / BCR-ABL fusion gene form the peripheral blood confirm the diagnosis. A bone marrow examination is usually not required. The bone marrow examination can be done in equivocal cases, to look for other chromosomal abnormalities or to assess the prognosis of the disease. -The leukocyte alkaline phosphatase (LAP) score may be used if the diagnosis is confused with reactive leukocytosis, in which WBCs are increased in response to infectious or inflammatory conditions. In CML, the LAP score is low, while in reactive leukocytosis, the LAP score is high.

Detection of monoclonal immunoglobulins/light chains:

-Electrophoresis: (Quantitative but not qualitative) /Serum protein electrophoresis (SPEP) /Urine protein electrophoresis (UPEP) -Immunofixation (immunoelectrophoresis): Qualitative but not quanitative -Serum free light chain (sFLC) assay

treatment of CML:

-First‐line therapy for patients with chronic phase CML is usually imatinib, nilotinib or dasatinib -Bosutinib is also an effective second line therapy, whilst ponatinib has the unique advantage that it is effective against tumours that carry the T315I mutation within BCR‐ABL1. -other treatment options: hydroxyurea, IFN-a, allogenic SCT

List chemotherpay drugs used to induce remission in ALL:

-Vincristine -Corticosteroids -Asparaginase -Danurubicin

Therapy of CLL:

-Generally, an indication for therapy is aligned regarding symptomatology, so that a lymphocytosis by itself does not present a reason for medicinal treatment -As first-line therapy, the FCR-regimen is applied in patients in good general condition and especially young patients. Thereby, Fludarabin out of the group of purine analogs is combined with cyclophosphamide out of the group of alkylating agents and Rituximab, a CD20-antibody. -The CD52-antibody Alemtuzumab is used in a subgroup of CLL having a worse prognosis due to a deletion 17p13 -Patients having a reduced general condition or organic dysfunctions are primarily treated with chlorambucil or bendamustine. Both substances are alkylating agents with fewer side effects like granulocyto- or thrombocytopenia. Bendamustine is also combined with Rituximab according to the BR-regimen. -A relapse after 2 years is often treated by repeating first-line therapy. Depending on the patient's condition and the genetic and immuno-phenotypical type of CLL, alternative types of therapies are planned. -Furthermore, in cases of therapy refractory CLL or high-risk patients, allogenic stem cell transplantation comes into consideration, which, however, is likewise associated with high mortality risk.

General features of monoclonal gammopathy of undetermined significance (MGUS):

-Genetically altered plasma cells (precancerous state) -Diagnostic criteria: /Serum M-protein less than 30g/l /Bone marrow plasmacytosis less than 10% /No end-organ damage /No evidence of amyloidosis or lymphoma -It has 1-2%/year risk of progression to multiple myeloma -It needs to be followed up every 6-12 months

Management of tumor lysis syndrome:

-Hydration -Allopurinol OR rasburicase -Sodium bicarbonate to alkalinize the urine -Potassium and calcium dietary restrictions

Serum changes in Tumor lysis syndrome:

-Hyperuricemia -Hyperkalemia -hyperphosphatemia -hypocalcemia -fatal acute renal injury

Pathogenesis of ALL:

-In ALL, there is a block in an early stage of stem cell differentiation. This results in an unchecked monoclonal multiplication of immature leukemic blast cells, which precedes the block. -These monoclonal leukemic cells occupy most of the bone marrow space, suppressing the production of normal hematopoietic cells. The leukemic cells of the hypercellular bone marrow then spill into the blood circulation and are visible on routine CBCs. -The decreased level of normal blood cells is responsible for most of the clinical symptoms. Decreased platelet levels cause bleeding. The decrease in red blood cell count leads to anemia and pallor, while decreased levels of normal white blood cells lead to severe recurrent infections.

Diagnosis of CLL:

-In the diagnostic investigation of the CLL, the first suspicion is made by often an accidental finding of a leukocytosis. In the subsequent differential blood count, typically, an increased percentage of lymphocytes are found, usually between 70 to 95%. -Bone marrow cytology is not necessarily required for diagnosis but can support a suspect of CLL in cases with a percentage of 30% or more mature lymphocytes among all nucleated cells. -The mature lymphocytes of the CLL are analyzed by using flow cytometry regarding their immunophenotype. The expression of the B-CLL surface proteins CD19, CD20 and CD23 with simultaneous expression of the T-cell antigen CD5 is characteristic for a leukemic population of lymphocytes. -

Pathophysiology of AML:

-In the earlier stages of AML, there is developmental blockage of the myeloid cells; in CML, this blockage occurs in a later stage. These immature myeloid cells (blast cells) are present in the bone marrow and enter the peripheral circulation. A minimum of 20% of blast cells is required for the condition to be diagnosed as AML -Chromosomal mutations can also result in the development of AML. Translocation of t(15:17 ) causes acute promyelocytic leukemia. This results in a fusion of the retinoic acid receptor on chromosome 17 with a PML gene on chromosome 15. The fusion product blocks the maturation in the promyelocytic stage, resulting in acute promyelocytic leukemia. Administration of retinoic acid in acute promyelocytic leukemia can overcome this block and can be used in the treatment of acute promyelocytic leukemia.

Pathogenomics of AML:

-Intracytoplasmic rods are seen in the myeloblasts. They have the following characteristics: /Composed of abnormal lysosomes /Stain with Sudan Black b stain /Myeloperoxidase positive -Histochemistry: Myeloperoxidase positivity indicates the presence of granulocyte differentiation. Auer rods are typically positive for myeloperoxidase. Non-specific esterase positivity indicates the presence of monocyte differentiation. -Immunochemistry This will indicate the presence of myeloid differentiation markers CD13, CD14, CD15, and CD64.

Diagnosis of AML:

-Laboratory findings include the following: /WBC count ranging from 10,000 cells/mm3 to 100,000 cells/mm3 along with the presence of blast cells /Anemia: Usually normocytic or macrocytic in the presence of a folic acid deficiency /Thrombocytopenia /Bone marrow findings show the presence of blast cells. A finding of dry tap indicates extensive fibrosis or hypercellular bone marrow. -The diagnosis of AML can be presumed through a finding of leukemic blast cells in the peripheral smear. Definitive diagnosis is based on the presence of bone marrow aspiration and biopsy. Immunophenotypic, morphologic, and cytogenetic studies are required for the subclassification of AML and for accurate treatment.

Features of Bence-Jones proteins:

-Light chain excreted in urine which precipitate at 60-70C, then dissolves over 70 C. -Can present due to: /Light Chain excess over reabsorbing capacity of kidney /kidney damage leading to impaired filter or absorbtion function -in plasma cell neoplasms they present in the urine with amount of more than 10mg a day.

List clinical features of lymphomas (NHL):

-Lymphadenopathy -Cytopenias -Systemic symptoms -Hepatosplenomegaly -Fever -Night sweats

Therapy strategy of multiple myeloma:

-MGUS, Smouldering MM: treatment not recommended (might change in close future) -Solitary Plasmacytoma -operation/radiotherapy -Therapy individualized: /Disease biology (cytogenetics!) / Patient characteristics (age, comorbidities) -Shifting from classic chemotherapy towards biological therapy -Moving towards continuous treatment strategy (multiple subclone, clonal evolution)

Differential diagnosis of CLL:

-Monoclonal B-lymphocytosis -CML -Mantle cell lymphoma

Criteria that confirm the diagnosis of CLL:

-More than 5,000 clonal B-lymphocytes/µL in the peripheral blood -Predominantly small, mature looking lymphocytes in cytological diagnostics -Expression of the B-cell antigens CD19, CD20, CD23, and the T-cell antigen CD5 -Light chain restriction to provide evidence for monoclonality

Symptoms of AML:

-Physical examination findings for AML include increased oozing of blood from the intravenous line and ecchymosis. This finding indicates the presence of disseminated intravascular coagulation -The presence of papilledema, retinal infiltrates, and cranial nerve palsy indicate the presence of central nervous system involvement. -Monocytic leukemia most commonly presents with gum hypertrophy and skin nodule formation -Pancytopenia is the most significant cause of most AML symptoms, including general weakness and increased infections and episodes of bleeding, especially from the gums and epistaxis. -Bone pain in AML is due to the expansion of the medullary cavity in both the upper and lower extremities. -Findings in the skin include the presence of petechiae ecchymosis due to thrombocytopenia and pallor due to anemia. -Joint pain occurs due to the presence of increased deposition of uric acid in the joints, resulting in gout. There is also a possibility of joint synovial infiltration by the neoplastic cells, resulting in joint pain.

General features of multiple myeloma:

-Proliferation of genetically abnormal monoclonal plasma cells in the bone marrow (more than 10%), and/or presence of monoclonal paraprotein in blood and/or urine (more than 0,5g/day) -Leads to organ damage: kidney, bone, bone marrow, nervous system, immune system, etc. -Median age is 60-70 years. More in african males -Expected overall survival is few months to 10 years.

treatment options in CLL:

-R-FC (Rituximab-Fludarabinem chlorambucil) is the first line treatment for younger patients -Bendamustine can be used (less immunosupressive) -Alemtuzumab (anti-CD-52), Used in case of resistance or relapse -New agents: /Ibrutinib (for tumors carrying 17p deletion or p53 mutation). /Idelalisib (block PI3K) -other treatments: corticosteriods, radiotherapy, lenalidomide, cyclosporine, immuneglobulins, SCT

Treatment of AML in young adults:

-Regimen 1: cytarabine plus daunorubicin. /Standard 7+3 regimen—administration of cytarabine for the first 7 days and daunorubicin for the first 3 days (daunorubicin is discontinued after the first 3 days). This therapy achieves 60—80% remission with minimal toxicity. -Regimen 2—administration of cytarabine plus idarubicin. Dosing schedule for cytarabine includes twice-daily dose for 12 doses along with idarubicin. -Idarubicin is administered immediately following idarubicin on the first 3 days. This regimen achieves a 90% remission rate but has substantial toxicity. Cytarabine and idarubicin show higher rates of remission compared with cytarabine and daunorubicin.

Therapy of AML:

-Remission induction therapy includes an initial course of intensive chemotherapy aimed at complete remission of AML. This is followed by post-induction chemotherapy. -A bone marrow transplant is used in resistant cases and on a case-by-case basis. -Younger adults will have better survival rates than those who are older.

treatment of ALL:

-Remission induction: Steroids, vincristine and asparaginase -Intensification (consolidation): Vincristine, cyclophosphamide, cytosine arabinoside, daunorubicin, etoposide, or mercaptopurine -CNS prophylaxis: intrathecal methotrexate -Maintenance: Mercaptopurine, methotrexate, vincristine, dexamethasone

Agents used in the treatment of multiple myeloma:

-Thalidomide, Lenalidomide and Pomalidomide (Side effects: polyneuropathym cardiac, GI symptoms and DVT/PE) -Protesome inhibitors: Bortezomib, carfilozomib, marizomib (Side-effects: polyneruopathy) -Steroids: dexamethasone -Alkylating agents: melphalan, cyclophosphamide -Anthracyclines: doxorubicine, adriamycin -Monoclonal antibodies: for relapses / Daratumumab - CD38 / Elotuzumab - SLAMF7

Prognosis of CML:

-The adequate treatment with imatinib increases the 5-year survival rate of chronic phase CML to more than 90%. Patients with accelerated phase/blast crisis have a very poor outcome and it is the major cause of death with an average survival of less than 1 year. -Some of the poor prognostic factors of CML are as follows: /Old age /Absence of Philadelphia chromosome / BCR-ABL fused gene /Increase blasts (accelerated phase/ blast Crisis) /Delay in achieving hematologic remission /Short duration of hematologic remission /Splenomegaly /Anemia /Thrombocytopenia/thrombocytosis /Basophilia

General features of CLL:

-The chronic lymphocytic leukemia (CLL) is the most common type of leukemia and belongs, being a leukemic B-cell-lymphoma, to the group of low grade, indolent non-Hodgkin lymphomas. Clonal proliferation of the usually non-immunocompetent B-cells induces accumulation in the bone marrow, the spleen and lymph nodes and causes leukocytosis in the peripheral blood. -The disease usually becomes manifest at a higher age and shows a slow progression of symptoms, so that initially a therapy often may be disclaimed. -Today lymphocytic proliferative leukemia, which originates from T-cells, is not called T-CLL anymore. This disease is named T-cell prolymphocytic leukemia and often presents a severe progression. -CLL, having an incidence of 4 per 100.000/year, is the most common of all types of leukemia. Age distribution of the disease's onset shows a clearly increasing incidence at higher ages. The mean age at the point of diagnosis is about 70 years and men are affected more often than women.

Classification of myeloid neoplasms:

1-Acute myeloblastic leukemia (AML) 2-Myelodysblastic syndrome 3-Chronic myeloproliferative disorders: a-polycythemia vera b-Essential thrombocytosis c-myelofibrosis d-Chronic myeloid leukemia (CML)

Main aims of therapy of CML:

1-Hematologic remission: Normalization of blood counts and splenomegaly 2-Cytogenetic remission: Disappearance of the Philadelphia chromosome on Karyotyping 3-Molecular remission: Negative PCR/FISH for BCR-ABL fused gene

Phases of the specific treatment of ALL:

1-Remission induction: /Aim is to induce complete remission by destroying most the leukemic cells /Most effective chemotherapies used are Vincristine, corticosteroids, asparaginase and danuorubicin /This phases lasts 4 to 6 weeks (the sooner the remission achieved the better the prognosis is) /CNS prophylaxis: intrathecal chemotherapy, intracranial radiation, high doses of methotrexate) 2-Remission Consolidation: /Repetitive cycles of combination chemotherapy are still continued for 6-9 months to kill any remaining residual malignant cells and avoid relapse. /In case of poor prognosis, BM transplantation can be performed in this phase. 3-Remission maintenance: /Repetitive cycles of oral chemotherapy for up to 3 years

list some poor prognostic factors in multiple myeloma:

1. Age 2. Bad performance state (ECOG,Karnofsky) 3. Comorbidities 4. High ISS score 5. Renal impairment 6. M-prot. other than IgG 7. High LDH, CRP 8. High risk chromosomal aberrations: t(4;14), t(14;16), del(17p),+1q, -1p, hypodiploid

Phases of CML:

1. Chronic Stable Phase It is the most common indolent clinical phase of CML. This phase is stable and lasts for many years. The myeloid cells are differentiated, with a presence of less than 10% of blast cells. The response to therapy is excellent. 2. Accelerated Phase The untreated CML usually progresses to the accelerated phase. The cells multiply aggressively and the blast cells increase in the blood usually between 10-19%. The response to therapy is poor. 3. Blast Crisis The accelerated phase progresses to the blast crisis. This phase is indistinguishable from acute leukemia with blast cells more than 20%. The response to therapy is very poor.

Translocation in acute promyelocytic leukemia:

15:17 - the retinoic acid receptor (RAR) is disrupted, leading to an accumulation of promyelocytes *treat with all-trans retinoic acid!

which leukemia is TdT+?

ALL (marker of pre-T and pre-B cells)

Auer rods seen in

AML

Main diagnostic criteria of acute leukemias:

Acute leukemia is diagnosed with hypercellular bone marrow containing >20% blast cells,

Which leukemia is associated mostly with philadelphia chromosome:

CML is classically associated with the Philadelphia chromosome (BCR-ABL fusion gene) and has an excellent prognosis with modern therapy.

Epidemiology of CML:

CML is common in middle and old age people, accounting for around 20% of all adult leukemia cases. The median age of presentation is 55 years.

DIC is mostly associated with which leukemia:

Acute promyelocytic leukemia (AML-M3)

What is the most accurate test to confirm multiple myeloma:

Bone marrow biopsy

Teardrop RBCs characteristic of:

Bone marrow infiltration (myelofibrosis)

Herpes zoster infection is associated with which leukemia:

CLL

which leukemia has smudge cells?

CLL

which leukemia is mostly associated with autoimmune hemolysis:

CLL

which leukemia is mostly associated with lymph nodes enlargement:

CLL

What is the most common leukemia in adults:

CLL (chronic lymphocytic leukemia)

which leukemia may have thrombocytosis:

CML

Cytosine Arabinoside (Cytarabine)

Cytarabine is mainly used in the treatment of acute myeloid leukaemia, acute lymphocytic leukaemia (ALL) and in lymphomas

The most common genetic disorder to be clearly associated with an increased risk of ALL is

Down syndrome

Do we have lymphadenopathy in AML:

IT IS RARE

Symptoms of CML:

In the early chronic stable phase, CML does not behave like a malignant disease. Quantitatively WBCs are increased, but they are differentiated and mature, and combat the infections. Patients may present with non-specific symptoms of low-grade fever, malaise, night sweats, or abdominal fullness and early satiety due to an enlarged spleen. Spleen size roughly correlates with the WBC count and massive splenomegaly corresponds to poor prognosis. Hepatomegaly is also common, but lymphadenopathy is usually not present. In 25% of cases, patients are asymptomatic and CML is diagnosed on routine blood tests or palpable spleen on physical examination. In accelerated phase and blast crisis, the patient presents like acute leukemia with fever, bleeding, petechiae, ecchymosis, and pallor due to overexpansion of bone marrow with the blast cells and ineffective production of platelets and red blood cells. The patient may also have bone tenderness and splenomegaly due to extra-medullary hematopoiesis. Rarely, patients may present with symptoms of leukostasis such as confusion, blurred vision, respiratory distress, thrombosis, headache or priapism, with WBC count usually >500,000/mcl. It is a medical emergency and should be urgently treated with leukapheresis and judicious hydration.

Treatment of AML in old patients:

Induction chemotherapy is performed with anthracycline and cytarabine; this differs from other chemotherapy regimens.

Myelodysblastic syndrome:

It is a pre-leukemic syndrome characterized by abnormal morphology (dysplasia) of myeloid cells. For example, the granulocytes have decreased intracytoplasmic granules. The neutrophils have only two-lobed nuclei, called Pelger-Huet cells. The megakaryocytes are dwarfed. The RBCs are large, oval and show ringed sideroblastic iron staining pattern. Because of such abnormal shapes, these cells are destroyed before releasing into the peripheral blood circulation, leading to cytopenias and hypercellular bone marrow.

What is a leukemic leukemia:

It is a type of acute leukemia in which blast cells are absent in peripheral blood but present in bone marrow (> 20 %).

Neutropenic enterocolitis

Neutropenic enterocolitis should be considered when the absolute neutropenia count is < 500/microL. It is usually diagnosed following chemotherapy. The clinical presentation involves lower quadrant abdominal pain associated with distension. Treatment involves providing supportive measures.

Prognosis of CLL:

Prognosis of a diagnosed chronic lymphocytic leukemia is significantly depending on the disease's stage and cytogenetics. Progress can be at a minimum level for years so that a lifelong "watch and wait" strategy can be maintained. Likewise, an aggressively proceeding form can progress into death quickly. The median survival of CLL that has been diagnosed in stage Binet A is above 10 years, in stage C below 3 years

Would you see splenomegaly in CML?

Splenomegaly is nearly always present and may be massive

Main treatment of CML:

The discovery of specific tyrosine kinase inhibitors, such as imatinib, dasatinib, and nilotinib, has revolutionized the treatment and prognosis of chronic myelogenous leukemia. They inhibit the BCR-ABL specific tyrosine kinase and cause apoptosis of these cells. These drugs are well tolerated and achieve the hematologic remission of chronic phase CML in 95% of cases and complete cytogenetic remission in 76% of cases after 18 months of treatment, but the molecular remission is achieved in only 26% of cases. These drugs also delay the progression of the chronic phase of CML to the accelerated phase and blast crisis, but they should be taken continuously as their discontinuation leads to relapses. In newly diagnosed CML, the prognostic milestones are set to achieve the complete hematologic remission in 3 months and the complete cytogenetic remission in 18 months of treatment. If these are not achieved, the treatment regimen has to be re-assessed. In an accelerated and blast crisis, there is a much lower response to imatinib and related drugs. In these cases, higher doses of drugs are given and bone marrow transplantation is advised to cure the disease. The supportive therapy with empiric antibiotics, red cell, and platelet transfusions may also be needed.

list some of the criteria that support the diagnosis of AML:

The following two criteria are required for an accurate diagnosis: -A minimum of 20% blast cells in the bone marrow aspirate or peripheral blood. Exceptions include t(8;21), t(15;17), and inv(16). -Documentation of the myeloid origin, which can be confirmed by the presence of the following: /Auer rods /MPO positivity /Myeloid markers

Mikulicz-syndrome

The rare Mikulicz-syndrome in CLL-patients denotes a swelling of the parotic gland and the lacrimal gland.

Duration of manifestation of ALL:

fast manifestation (days to weeks)

List the tyrosine kinase inhibitors.

imatinib, dasatinib, and nilotinib, (They inhibit the BCR-ABL specific tyrosine kinase and cause apoptosis of these cells.)

Acute lymphocytic leukemia common in which age groups:

in children (0-14 years)

Myeloid disorders associated with JAK-2 kinase mutation:

a-polycythemia vera b-Essential thrombocytosis c-myelofibrosis

List different types of multiple myeloma:

a. Active (symptomatic) MM b. Smouldering (asymptomatic) SMM c. Plasma cell leukaemia d. Non-secretory MM (NSMM)

Acute myeloid leukemia is common in which age group:

common in adolescence but also in younger children

Follicular lymphoma genetics

t(14,18) translocation of heavy chain Ig and bcl-2 bcl-2 inhibits apoptosis

Ritcher's transformation

transformation ofCLL to diffuse large B cell lymphoma (DLBCL)

Diagnosis of NHL:

•Excisional biopsy is preferred to show nodal architecture (follicular vs diffuse). •Immunohistochemistry to confirm cells are lymphoid -LCA (leukocyte common antigen)CD45 -Monoclonal staining with Igk or Igl •Flow cytometry:-CD19, CD20, CD79afor B cell lymphomas-CD3, CD4, CD8 for T cell lymphomas