7ALL Treatment Protocol 24 mo PTA22 mo PTA20 mo PTA17 mo PTA16 mo PTAPhase IPhase IIPhase IIIPhase IV (1)Phase IV (2)VincristineDoxorubcinL-aspPrednisone6-MPCyclophos.Ara-CIT MTXXRT-CNSDoxorubicinDexa6-TGFebrile NeutropeniaBM Bx : NLFlow : NLFebrileNeutropeniaHLA-MatchDonorBM Bx : CRAcyclovir, Fluconazole
8Past History 15 mo PTA : ALL protocol Phase V 6–MP (50 mg) 2*1 -> ½ * 1 OD (due to pancytopenia)Metrothexate (2.5 mg) 13*1 -> 6*1 OWCo-trimoxazole 2*1 twice a weekAcyclovir (200) 1*3 thrice a week
9Past History1 เดือน PTA: มาตรวจตามนัด สบายดี น้ำหนักปกติ (BW 62 Kg) PE: no hepatosplenomegaly- CBC: WBC 3,240 (N 54%, L 25%, Mo 11%), Hb 13.8, Hct 40% MCV 113, RDW 17, Plt 203,000, no blast cell- BM study : complete remission- Flow cytometry: no detectable leukemia cell
10Physical examination A young Thai male, febrile, no tachypnea V/S : BT 39.5°C, RR 18/minBP 110/60 mmHg, PR 96/minSkin : diffuse mild erythematous papules both exposed sites of arms and legs
11Physical examinationHEENT: No pale conjuctivae, no icteric sclerae, no oral candidiasis , mild enlarged non-inflamed tonsils, multiple bilateral posterior cervical, axilla and epitrochlear lymph nodes size cm in size
13Physical examinationHeart : PMI at Lt 5th ICS, MCL, regular, normal S1,S2, no murmurLungs : clearAbdomen : no distension, active BS, soft, not tender, liver 1 cm below RCM, sharp edge, not tender, firm, span 12 cm, spleen 2 cm below left costal margin, not tenderExtremities : no edema, no eschar
14InvestigationCBC: Hb 13.6, Hct 39.7%, MCV 106, RDW 14.6, WBC 3,430 (N 86.3%, L 11.4%, M 1.7%, Eo 0.3%, B 0.3%), Plt 53,000PT 13.5, INR 1.2, PTT 32.6BUN/Cr: 4/0.64LFT: TB/DB 0.5/0.14, AST/ALT 37/69, ALP 85, globulin 2.4, albumin 4.0UA: WBC 0, RBC 0, Protein: neg, Sugar: negU/C: NG , H/C: NG x IIAnti-HIV: negative
16Treatment with Ceftazidime 2 g IV q 8 hr were given together with G-CSF 480 mcg SC OD. Diagnostic tests were performed.
17Cardinal FeaturesA young man with protracted course of fever, malaise, erythematous rash, enlarged tonsils, generalized lymphadenopathy and hepatosplenomegalyLeukopenia and thrombocytopenia with atypical lymphocytosisAcute or subacute viral infectionMononucleosis-like syndrome?
18Atypical LymphocytesFirst distinguished morphologically from leukemic lymphoblasts by Downey and McKinlay in 1923.
19Atypical Lymphocytes At least 4 types are easily recognizable Typical monocytoid atypical lymphocytes: activated CD8+ T cellsPlasmacytoid atypical lymphocytes: activated B cellsLarge granular lymphocytes: cytotoxic T or NK cellsLymphoblastoid atypical lymphocytes: any activated cells about to enter cell division or viral-transformed B or T cells
298 days PTA Exposure to แตนทะเล then fever with rash ไข้ลดลง ผื่นยุบ Fever with chillsAdmit นครธนAdmit นครธน8 days PTA3 days PTA5 days PTAKCMHHb 13, WBC 1500, N 76%, L 15%, plt 150,000H/C NG x I, U/C NGWBC 2500N 73%, L 15%Hb 13.6, WBC 3430, N 86%, L 12%, plt 53,000Ceftazidime+Amikacin+G-CSFMoxifloxacin 400 mg iv ODMoxifloxacin po
30Classical Description of Infectious Mononucleosis From Wintrobe’s Hematology 10th Edition, pp ;reproduced from Carter PL, Penman HG. Infectious Mononucleosis, 1969.
32Algorithmic approach to mononucleosis-like illnesses Hurt C, Tammaro D. Diagnostic evaluation of mononucleosis-like illnesses. Am J Med 2007;120:911-
33What’s wrong with the pattern recognition approach to complex medical problems? Requires careful characterization or classical presentation of each symptom in “triads”, “tetrads” or “pentad” of diagnostic criteriaSensitivity and specificity increase with the numbers of typical featuresBeware mimicry of S&S by other causes or syndromesModification of S&S by underlying, associated diseases or treatmentsGive no insight into the pathogenesis of diseases or syndromes
34Additional Features History of exposure to แตนทะเล (sea wasp?) History of exposure to moxifloxacinPre-B ALL in remission on maintenance chemotherapySensitive to myelosuppressive effects of ethotrexate and 6-mercaptopurine
35แตนทะเล = Sea Wasp or Box Jellyfish? “Box jellyfish are best known for the extremely powerful venom possessed by some of their species. The Chironex fleckeri and the Carukia barnesi (Irukandji) species are the most venomous creatures in the world. Stings from such species are excruciatingly painful, either initially or as an after-effect, and are often fatal.”From Wikipedia accessed at
39EBV-associated lymphoproliferative disease and mosquito bite allergy Hypersensitivity to mosquito bite (HSMB) has been recognized as a spectrum of EBV-associated diseases, especially in the Far East (Japan and Korea)Patients are predisposed to develop hemophagocytic syndrome and clonal EBV- associated lymphoproliferative disease (usually NK or T/NK lymphoma)J Dermatol Sci. 2007;45(3):
40Pathogenesis of HSMB Poorly understood and studies Usually increased EBER+ CD16+/CD56+ NK cells in peripheral bloodAugmented CD4+ T cells response to EBVJ Dermatol Sci. 2007;45(3):
41Additional Features History of exposure to แตนทะเล (sea wasp?) History of exposure to moxifloxacinPre-B ALL in remission on maintenance chemotherapySensitive to myelosuppressive effects of ethotrexate and 6-mercaptopurine
428 days PTA Exposure to แตนทะเล then fever with rash ไข้ลดลง ผื่นยุบ Fever with chillsAdmit นครธนAdmit นครธน8 days PTA3 days PTA5 days PTAKCMHHb 13, WBC 1500, N 76%, L 15%, plt 150,000H/C NG x I, U/C NGWBC 2500N 73%, L 15%Hb 13.6, WBC 3430, N 86%, L 12%, plt 53,000Ceftazidime+Amikacin+G-CSFMoxifloxacin 400 mg iv ODMoxifloxacin po
43Is there any relationship to moxifloxacin exposure? No case of mononucleosis-like illness has been reported in patients receiving moxifloxacin in the literatureAntibiotics-induced erythematous rashes in infectious mononucleosis are well- known for beta-lactam (especially amoxicilllin) but were also reported in macrolides, doxycycline and quinolones
44Picture from Sandoz Atlas of Clinical Haematology 1994. Morbilliform erythematous eruption in infectious mononucleosis after exposure to amoxicillin.Picture from Sandoz Atlas of Clinical Haematology 1994.
45Additional FeaturesHistory of exposure to แตนทะเล (sea wasp?) and moxifloxacinPre-B ALL in remission on maintenance chemotherapy Is it relapsed?Sensitive to myelosuppressive effects of ethotrexate and 6-mercaptopurine
48Estimated Frequencies of Specific Genotypes in ALL Figure 2. Estimated Frequencies of Specific Genotypes among Children and Adults with ALL.The data are from studies at St. Jude Children's Research Hospital4,8 and from the Groupe Francais de Cytogenetique Hematologique,5 Chessells et al.,6 and Copelan and McGuire.7Pui, C.-H. et al. N Engl J Med 1998;339:
49Poor prognostic factors in ALL B-lineage ALLAge > 50 yearsWBC > 30,000/LPro-B ALL (CD10-)t(9;22)[BCR/ABL]t(4;11)[AF4/MLL]CR > 4 weeksT-lineage ALLWBC > 100,000/LEarly-T or mature-TCR > 4 weeksGerman Multicenter ALL Group 2000
50Outcomes of ALL treated by standard protocol Thomas, X. et al. J Clin Oncol; 22:
51TREATMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) Induction chemotherapyCombination of VCR, ADR, Pred +/- cyclophosphamide and L-asparaginase in 8-12 weeksShort-course intensive chemotherapyPost-remission therapyConsolidationIntensificationMaintenanceStem cell transplant (Auto or Allo SCT)CNS prophylaxis and treatment
52Induction chemotherapy for ALL Modified from BFM protocol (Hoelzer et.al. Blood 1988)
57Post-remission therapy Standard-risk: no bad prognostic factorStandard consolidation chemotherapy, maintenance and CNS prophylaxisStem cell transplant in second CRHigh-risk: at lease one poor prognostic factor except Ph chromosome or MRD+ after inductionIntensified chemotherapyStem cell transplant, preferably allogeneic, in first CRVery high-risk: Ph+ ALLAllogeneic stem cell transplant in first CRSearch for unrelated donors or cord blood if no siblingsExperimental therapy - autologous stem cell transplant with imatinib or antibody-purged grafts
58Allogeneic SCT for high-risk ALL Thomas, X. et al. J Clin Oncol; 22:
59Allogeneic SCT in first CR also improve outcomes of standard risk ALL (MRC UKALL XII/ECOG E2993) Blood 2008; 111:
60How possible is relapsed ALL? 1 month prior, he was still in remission with normal bone marrow study including flow cytometry for minimal residual diseaseCBC now shows relatively preserved marrow function.Peripheral blood smear reveals no blast cellsRelapse is, therefore, unlikely at this point but still requires bone marrow study for exclusion
61Why is he so sensitive to MTX and 6-MP? His dose of maintenance chemotherapy:6–MP 25 mg daily and MTX 15 mg weekly ~ 50% reduction.
63TMPT Polymorphism and Outcomes of ALL Treatment with Standard Chemotherapy About 1 in 300 individuals inherit TPMT deficiency as an autosomal recessive trait.Three particular TPMT alleles, designated as TPMT*2, TMPT*3A, and TPMT*3C, have been shown to account for nearly 95% of the observed cases of TPMT deficiency.Patients who carry TPMT polymorphisms are at risk for severe hematologic toxicities when treated with 6-MP because these polymorphisms lead to a decrease in the rate of 6-MP metabolism6-MP dose intensity is a significant predictor of event-free survival in children with acute lymphatic leukemia (ALL)
64TPMT Polymorphism in Thai Population Hong-Eng et al. studied in 75 Thai children with acute leukemia. The frequency of TMPT heterozygote was 11%. TPMT*3C was the only allele found in Thailand.1Subsequent study in general population also confirmed this finding.21 Hongeng et al. Med Pediatr Oncol Oct;35(4):410-42 Srimartpirom et al.Br J Clin Pharmacol. 2004; 58:66–70.
65How about the effects of methotrexate? MacrocytosisMegaloblastic changes in bone marrowPotentiate bone marrow suppression effects of 6-MPPredispose to EBV-associated lymphoproliferative disease
68My Clinical DiagnosisPrecursor B-lymphoblastic leukemia in complete remissionTPMT deficiency due to genetic polymorphism TMPT*3C alleleAtypical lymphoproliferative disease, probably EBV-associated
69Further investigation Bone marrow study: aspirate, biopsy and immunophenotypingLymphocyte subset study and clonal determination by flow cytometry or TCR and/or Ig rearrangement analysisAbdominal imaging either by CT or ultrasoundEBV Anti-VCA IgM, IgG, anti-HHV-6 IgM, IgGEBV-DNA, CMV-DNA, HHV-6 PCR?