Initial Workup of Acute Leukemia Draft Recommendations with Comments - 9/1/2015. What is your occupation/role? (Select all that apply)

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1 What is your occupation/role? (Select all that apply) Hematologist Pathologist Oncologist Nurse Medical Director Technologist/Te chnician Laboratory Manager Hospital Administrator Patient Advocacy Gro... Patient Other (please specify) 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Answer Choices Hematologist Pathologist Oncologist Nurse Medical Director Technologist/Technician Laboratory Manager Hospital Administrator Patient Advocacy Group Representative Responses 39.04% % % % % % % % % 0 Patient 0.00% 0 6 / 99

2 Other (please specify) 11.40% 26 Total Respondents: 228 # Other (please specify) Date 1 consultant for clinical utility of ldt for medicare coverage of molecular tests 8/31/ :55 AM 2 head of laboratory for cytogenetic and molecular diagnosis 8/31/ :16 AM 3 cytogeneticist 8/31/ :12 AM 4 Hematopathologist 8/30/2015 8:20 PM 5 Pediatric Hematologist/Oncologist (encompassing two chosen above) 8/30/2015 5:56 PM 6 emerituschairman ology and medical director, dept of p[athology 8/28/ :49 AM 7 Manufacturer 8/27/2015 9:26 AM 8 The COG Myeloid Disease Committee is submitting a single reponse. 8/26/ :45 AM 9 MD 8/26/2015 9:51 AM 10 Clinical geneticist in training 8/26/2015 2:33 AM 11 Hematopathologist 8/25/2015 9:52 PM 12 MD 8/25/2015 3:46 PM 13 MD 8/25/2015 2:14 PM 14 NCCN BIomarkers Compendium writer 8/21/2015 3:57 PM 15 pediatric oncologist 8/20/ :09 AM 16 Resident in Medical Genetics focusing on hematological malignancies 8/20/2015 2:25 AM 17 Molecular biologist 8/20/2015 1:05 AM 18 pediatric oncologist 8/19/2015 9:10 PM 19 Research Scientist 8/19/2015 3:25 PM 20 Laboratory Director 8/16/ :31 PM 21 Laboratory Director 8/16/ :28 PM 22 Nurse prcatitioner 8/13/2015 7:39 AM 23 Hematopathologist 8/12/2015 6:21 PM 24 Fellow 8/12/2015 9:17 AM 25 CYTOGENETIC DIRECTOR 8/11/2015 9:42 AM 26 medicine student 8/10/ :13 AM 7 / 99

3 Which of the following best describes your practice setting? University hospital /... Voluntary, non-profit... Proprietary hospital City / County / State... Veterans hospital Army / Air Force / Navy... National / corporate... Regional / local... Public Health, non-hospital Clinic, group or doctor... Industry or vendor Other (please specify) 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Answer Choices University hospital / Academic medical center Voluntary, non-profit hospital Proprietary hospital City / County / State hospital Veterans hospital Army / Air Force / Navy hospital National / corporate laboratory Regional / local independent laboratory Public Health, non-hospital Responses 63.04% % % % % % % % % 0 8 / 99

4 Clinic, group or doctor office laboratory Industry or vendor Other (please specify) 2.17% % % 14 Total 230 # Other (please specify) Date 1 clinical concultant for medicare coverage 8/31/ :55 AM 2 Government (NIH) 8/31/ :11 AM 3 FDA 8/31/ :07 AM 4 NCI-Funded AML consortium 8/26/ :45 AM /26/2015 9:51 AM /25/2015 3:46 PM /25/2015 2:14 PM 8 locum 8/25/ :31 AM 9 Children's Hospital 8/24/2015 3:44 PM 10 non-profit cancer center alliance 8/21/2015 3:57 PM 11 retired 8/20/2015 2:00 PM 12 specialized pediatric oncology hospital 8/20/2015 5:01 AM 13 Private practice 8/19/2015 8:45 PM 14 Retired Pathologist MD AP & CP--now Lab Consulting only 8/10/2015 9:28 PM 9 / 99

5 Statement 1: The treating clinician should provide relevant clinical data or ensure that this is readily accessible by the pathologist.note: This includes, but is not limited to, age, gender, family history, history of prior malignancy and/or cytotoxic therapy, history of predisposing conditions, ethnicity, and clinical findings having prognostic importance. The treating clinician should also include history of any confounding factors, such as recent growth factor therapy or other medications or conditions that might obscure or mimic the features of acute leukemia. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Answer Choices Responses 97.09% % 6 Total 206 # Comment Date 1 It is critically import to include growth factor therapy in the medical history and it is most signifiant condounding factor. 9/1/ :01 AM 2 CBC and differential count should be specified as it is the most relevant lab data. 8/31/ :36 PM 26 / 99

6 3 Herein are our summary comments to this Draft: Dear Sir, Madam, We would like to take this opportunity to respond to the Draft Statements for the Initial Work-up of Acute Leukemia. There was a general feeling that if well-constructed and clearly stated, guidelines such as these will provide an excellent guide for clinicians and pathologists, particularly those that are establishing themselves, and/or who are not located at tertiary centers. However, as written, with interspersed may and should directives, the document is confusing, especially for those who may not be abreast of current basic science and clinical research literature. It is clear that many of the items listed are, at the present time, of no importance to clinical practice, and are essentially for research purposes only. We strongly suggest that the document be stratified accordingly, with the should items clearly listed first, followed by a second list of may directives that comprise the research items. In both cases, we feel that the document would be strengthened considerably if it provided links to the primary sources that establish the need for a given test for all but the most basic procedures, particularly the less routine molecular analyses. This concern that is derived from our opinion that many of the items being requested are of marginal or no current benefit to the patient and the treating clinician. This would be consistent with the guidelines in the WHO Classifacation of Tumours of the hematopoietic and Lymphoid Tissues where the emphasis is on tests that can be applied world wide. 1. Our group raised serious concerns about the necessity for chemistry assays and coagulation studies (Statement 3); these are not currently considered by us when making a diagnosis, and it is not clear if these will play an important role in aiding the clinician as we make a diagnosis. Perhaps the recommendation can be made more specific, so that it applies to only cases where acute promyelocytic leukemia is being considered. 2. Regarding Statement 7, the opinion of this group is that there is no need to perform flow cytometry to distinguish early T-cell precursor leukemias from T lymphoblastic leukemias in general; this distinction is not a part of the current W.H.O. classification, and, to our knowledge, has no implications for therapy. 3. Regarding statement 14, we object to the request that flow cytometry be performed so as to allow for detection of minimal residual disease. Such studies are outside of the capabilities of many laboratories, and a meaningful analysis can only be performed by specialized centers. 4. In statement 15, we take issue with the request for quantitative PCR analysis of BCR-ABL1 transcript on ALL patients with t(9;22). While it is important to document whether the transcript represents a major or minor form, there is no rationale for quantitation at diagnosis, since all cases are high. We are not aware of any study that proves the importance of this quantitation at the time of diagnosis. 5. Also regarding Statement 15, we feel it should be stated the FISH analysis of t(9;22) be performed rapidly (STAT) so as to allow for induction therapy that incorporates a TK inhibitor to commence in a timely manner. 6. Regarding Statement 17, we believe there should be further explanation to justify the mutational analyses of PAX5, JAK1, JAK2, and FBXW7. Can these be documented to be clinically indicated at the present time? If so, the studies that document the importance of these tests for clinical outcomes and treatment should be provided. 7. We would like some further clarification on Statement 18: to our knowledge, several of the recommended tests have no clinical impact, and evidence of such should be provided. For instance, mutational analysis of WT1 is of no impact. Similarly, gene expression analysis for ERG, BAALC, and EVI1 is without merit at the present time, since no metrics for high versus low expression have been established, nor have the implications for treatment been defined. 8. Also on Statement 18, we are of the opinion that FLT3-ITD mutation may be performed, rather than should be performed. 9. Regarding Statement 19, it is not clear why this is a separate statement, rather than being grouped together with Statement Statement 22 should be omitted, since at this stage, this is clearly an area of research rather than of clinical necessity. 11. Regarding statement 23, again, as indicated above in item 4, the quantitation of BCR-ABL1 transcript at the time of diagnosis is of no clinical importance and should be omitted. 12. It is our opinion that Statement 25 should be omitted, since performing tests at the primary institution can often save time and lead to more rapid initiation of treatment. We thank you for the opportunity to respond to this Draft. Sincerely, Archibald S. Perkins, MD. PhD Andrew Evans, MD. PhD Richard Burack, MD. PhD Marshall Lichtman, MD John Bennett, MD. Departments of Medicine and Pathology& Lab Medicine University of Rochester Rochester, NY 4 This is a general comment, not referred specifically to Statement 1: Today, on my first day of work after the summer holidays, I have been aware for the first time of the joint initiative of ASH-CAP to develop an evidence-based guideline for the initial work-up of acute leukemia and that today is the deadline for comment on the recommendations included in the draft. With such a tight time, I simply warn that I have observed two references by Roman-Gomez J et al (100, 101). These and many other papers by this author have been recognized fraudulent and therefore should be rejected by the scientific community. If I would have at least a couple of days, I would make some additional comments. For example, on the role that may have the anti-pml antibody in the rapid diagnosis of acute promyelocytic leukemia (Statement 20), as well as the recommended techniques for a genetic diagnosis of APL. 5 On occasion, patients are referred from outside institutions with cytogeneic and mutational testing done on outside platforms. These should also be included. 6 not specific enough, what family history, what cytotoxic therapy, what predisposing conditions what prognostic indicators 8/31/2015 4:42 PM 8/31/2015 3:37 PM 8/31/ :15 PM 8/31/ :59 AM 7 Peripheral blood counts should also be made available to the pathalogist 8/31/ :31 AM 27 / 99

7 8 Initial Work-up of Acute Leukemia Draft Statements We have attached all of our comments under statement 1. Thank you. General comments: We appreciate the hard work on this well-written and thorough document. We would however suggest that consideration be given to the intent of words used throughout the document that specify whether testing is required ( use: must to indicate this), is to be strongly considered ( use: should ), or is optional (use: could not may ). Abbreviation Section: It should be fluorescence not fluorescent. Statement 3: We suggest deleting and include any pertinent data in the final report. It is not always clear what may be pertinent from the potentially different perspectives of a pathologist versus a clinician or other member of the clinical team. In addition, there is the possibility for introduction of reporting errors and/or misinterpretation of the data. For example, an elevated D-dimer is not always indicative of DIC. Statement 6: We suggest substituting should for may because, although we recognize that not all materials are reviewed by a pathologist, they should be. Statement 7: a) We suggest deleting the word limited in front of immunophenotyping. While immunohistochemical studies may not be as completely robust as flow cytometry, an adequate and reasonable (not limited) workup and diagnosis can generally be performed and obtained. b) If T- lymphoblastic leukemia/lymphoma is the diagnosis, then we would recommend in addition to routine karyotyping (which is often normal) that FISH for cryptic abnormalities be performed. Statement 8: Delete suspected or. Statement 11: We would recommend adding a statement that if fresh tissue is not available, that paraffin-embedded material must be used for immunohistochemical, FISH, and molecular studies. ALL Statements Statement 12: a) For patients with central nervous system symptoms or signs, the treating clinician should obtain a cerebrospinal fluid sample. The treating clinician or pathologist should ensure that a cell count is preformed and that examination/enumeration of blasts on a cytocentrifuge preparation is performed. Is there a difference because this is a section on ALL? Is there a difference between pediatric and adult cases? Pediatric essentially always does CSF. adults? b) Delete suspected or. c) Take out treating clinician. Statement 13: Delete suspected or Statement 14: Delete suspected or Statement 15: a) Delete suspected or b) Second sentence. We would recommend that it is sufficient to determine the BCR-ABL1 transcript type, but that it is not relevant to quantify the transcript at diagnosis. Statement 16: a) Delete "suspected or b) Second sentence. We would recommend that it is sufficient to determine the BCR-ABL1 transcript type, but that it is not relevant to quantify the transcript at diagnosis. Statement 17: a) Delete suspected or b) We would recommend a significant alteration of this statement. It is not currently the standard of care to assess all B-ALL cases for these specific gene targets. Use of the word may (which implies permission) leaves the door open to unnecessary testing. In addition, the list of gene targets of clinical relevance is likely to undergo substantial revision in a relatively brief time frame because of rapid advances in the science, making any recommended list clinically irrelevant. Perhaps the recommendation could be that The pathologist or clinician could order assessments of other validated gene targets. The committee could then consider providing a link to an often updated site that has the latest information on the recommended clinically validated gene targets. AML Statements Statement 18: a) Delete everything after the first sentence b) Add: The pathologist or clinician could order mutational analysis of other clinically validated genes for prognostic or therapeutic purposes. The committee could then consider providing a link to an often updated site that has the latest information on the recommended clinically validated gene targets. Statement 21: We would suggest providing a link to a list of the myelodysplasia-related cytogenetic abnormalities. Statement 22: Remove statement. Not standard of care. Statement 23: We would recommend that it is sufficient to determine the BCR-ABL1 transcript type, but that it is not relevant to quantify the transcript at diagnosis. Where should testing be performed? Statement 24: Change should to must. 8/31/2015 8:44 AM 9 This information should be provided if it is not readily available in an accessible electronic medical record. 8/30/2015 8:26 PM 10 I think prior radiotherapy should be mentioned as well as prior cytotoxic therapy 8/28/2015 3:44 PM 11 I strongly support this statement. Valuable time is lost chasing the critical information before treating the patient There should be a rapport between clinician and pathologist and open communication aboutthe patient. 12 Initial clinical presentation/ reason for requesting medical attention (acute presentation with fever and bleeding manifestation versus routine annual check up). 8/28/ :11 PM 8/28/2015 6:57 AM 13 Attach a clinic note from a patient recent visit should serve much of the purpose and should be a requirement. 8/27/2015 6:57 PM 14 The following should be available: CBC with manual differential, LDH, uric acid, PT, PTT, fibrinogen. In addition to the clinical features listed above, physical findings such as lymphadenopathy, hepatosplenomegaly, skin infiltration, etc should be reported. It is also helpful to know the acuity of the patient's presentation. For example I have had a patient who was diagnosed by the pathologist with CMML however the patient deteriorated to the point of needing intubation in a few days. The patient had AML M5b. 8/26/2015 3:40 PM 15 Also other stimulatory medications like EPO, Thrombopoietin, etc which can cause dyspoietic changes in the marrow. 8/26/ :40 PM 16 Are these recommendations for children as well or only for adults? 8/26/2015 9:52 AM 17 I have often found, especially with referral patients, that important data has not yet been scanned into the EMR, but that the clinician has knowledge of this information. Sometimes this data has been crucial to making the correct diagnosis. 8/26/2015 6:55 AM 18 This information is often critical to appropriate test selection and specimen triage. 8/25/ :19 PM 28 / 99

8 19 Ensuring readily accessible data is not sufficient. Whose defination of "Readily Accessible" are we going to use? No ALL RELAVENT INFORMATION INCLUDING PAST MEDICAL HISTORY MUST BE SUBMITTED WITH THE SAMPLE! 8/25/ :15 PM 20 The EHR should help with this. 8/25/2015 9:48 AM 21 Often, the pathology requisition has little or no information written on it. 8/24/2015 3:52 PM 22 However, most of this is available in our EMR so is in this era redundant. 8/24/2015 3:47 PM 23 Clinical finding should include remote CBCs for longstanding abnormalities not previously appreciated (e.g., mild thrombocytosis or macrocytosis without anemia). 8/21/2015 6:40 PM 24 Consider adding any recent/prior history of infections (and for young patients/children) any exposure to EBV/mono. 8/20/2015 3:08 PM 25 This is nice, but not absolutely necessary. The synthesis of the laboratory findings, with the clinical features of disease and persence, or absence, of antecedent hematological disorder would be the job of the clinical practitioner. The information may be usseful to the Pathologist, but could potentially bias the pathologist as well. It is not pertinent to the Pathologist. 26 Also include history of recent severe or unusual infections which might cause leukemoid reactions and of course any syndromes or suspected syndromes in children 27 The more clinical history the better, especially if the clinician does not have notes on an electronic medical record. Having this history is vital to first triaging a specimen as well as diagnosing a leukemia. Bone marrows with a history suggestive of leukemia will be expedited ahead of other cases. Medication history is also vital because treatment with steroids or growth factors could lead to a misdiagnosis. 8/20/2015 1:21 PM 8/20/ :11 AM 8/20/2015 9:02 AM 28 Statement 1. I think prior radiotherapy should be mentioned as well as prior cytotoxic therapy. 8/20/2015 7:16 AM 29 Would also add comorbidity like serious illness, infection that could cause a leukemoid reaction 8/19/2015 9:12 PM 30 The statement should be stronger - i.e. for best patient care, the treating clinician should 8/19/2015 7:23 PM 31 The treating clinician and the pathologist should be in direct communication during the initial evaluation of the patient. 8/19/2015 4:44 PM 32 The treating clinicians should examine blood and marrow morphology 8/19/2015 4:19 PM 33 I have a cross appointment to the laboratory so I can speak as both a clinician and a pathologist, and I think clinical information is critical to expediting appropriate workup. 34 In a rapidly evolving situation, not all information is available in an EMR. Should a template (check list) be developed to identify key data for submission with diagnostic material. 8/19/2015 3:26 PM 8/18/2015 3:09 PM 35 But it is a tall order. Practically we have never received this much information. 8/18/ :01 PM 36 Family history is not well annotated in leukemia patients but is incredibly important - inherited leukemia predisposition syndromes are vastly under-diagnosed 8/17/ :28 AM 37 Include prior cytopenias and duration 8/17/ :18 AM 38 Is ethnicity important for the diagnosis of classification of acute leukemia? 8/13/2015 3:38 PM 39 It will be necessary specified the relevant clinical data, exists a lot of information that probably will generate a lot of confusion in this context 8/12/2015 3:55 AM 40 but should also include recent transfusions since these alter red cell and platelets counts 8/11/2015 7:15 PM 41 The history of prior malignancy should be as specific as possible. We get many specimens with "h/o leukemia" or "history of lymphoma", without specifying type of leukemia or lymphoma 42 Clinical history is very important. Also good to know what testing has already been performed to avoid duplicate testing. 8/11/ :16 AM 8/10/2015 3:26 PM 29 / 99

9 Statement 2: The treating clinician should provide relevant physical and clinical examination findings or ensure that these are readily accessible by the pathologist.note: This includes, but is not limited to neurologic exam findings and the presence of tumor masses, other tissue lesions (e.g., cutaneous), and/or organomegaly. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Answer Choices Responses 97.51% % 5 Total 201 # Comment Date 1 Ophthalmologic findings to exclude complications associated with hyperleukocytosis 9/1/2015 4:52 PM 2 be specific 8/31/ :59 AM 3 I think this is helpful but not essential. 8/31/ :10 AM 4 This information should be provided if it is not readily available in an accessible electronic medical record. 8/30/2015 8:26 PM 5 Physical and clinical examination findings is tautological. 8/28/2015 3:44 PM 6 this is essential and should be automatic... 8/28/ :11 PM 7 see above 8/27/2015 6:57 PM 8 see comment above. 8/26/2015 3:40 PM 9 Also report if patient has relevant CT findings such as organomegaly seen on CT (as opposed to physical exam), mediastinal mass, lymphadenopathy, etc 10 I have often found, especially with referral patients, that important data has not yet been reported in the EMR, but that the clinician has knowledge of this information. Sometimes this data has been crucial to making the correct diagnosis. 8/26/ :40 PM 8/26/2015 6:55 AM 11 See Above. Treating Clinician MUST PROVIDE relevant CLINICAL information! 8/25/ :15 PM 30 / 99

10 12 The EHR should help to ensure that these are readily accessible by the pathologist 8/25/2015 9:48 AM 13 Need to know about a mediastinal mass in an adolescent male with newly-diagnosed acute leukemia. Also, DIC manifestations for APML 8/24/2015 3:52 PM 14 Particularly for clinical signs of gingival infiltration or bleeding to suggest underlying DIC. 8/23/ :10 PM 15 There is an extra period that should be deleted at end of statement 2. 8/20/2015 3:08 PM 16 As above, it might be nice, but what training does the Pathologist have to interpret these physical findings. Even in purely extramedullary disease, how would these findings be interpreted by someone without clinical, bedside experience? It would not be useful. And remember, for those writing the guidelines, the document will be utilized in a medico-legal setting. 8/20/2015 1:21 PM 17 Statement 2. Physical and clinical examination findings is tautological. 8/20/2015 7:16 AM 18 Ideally this information should be in an electronic patient record and the entire electronic patient record should be available to the pathologist. 8/19/2015 5:37 PM 19 The treating clinicians should examine blood and marrow morphology 8/19/2015 4:19 PM 20 In a rapidly evolving situation, not all information is available in an EMR. Should a template (check list) be developed to identify key data for submission with diagnostic material. 8/18/2015 3:09 PM 21 also signs/symptoms of coagulopathy 8/17/2015 6:06 PM 22 Would have skin exam called out specifically in your "Note" 8/17/ :28 AM 31 / 99

11 Statement 3: The pathologist should review the results of chemistry assays and coagulation studies when available, and include any pertinent data in the final report. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Answer Choices Responses 79.00% % 42 Total 200 # Comment Date 1 Results of chemistry assays are not relevant. Results of coagulation studies can be important, but they are not of diagnostic value. 2 The statement is too vague if it is for a bone marrow report, and the type of report should be specified. It should define what chemical assays are necessary for including in a bone marrow report. Coagulation studies are good to review as DIC lab studies may help in the initial assessment of the presence of blasts. It is unclear however, what should be specified besides the CBC and differential count (statement 4) that actually adds anything to a morphologic marrow report. 3 that the pathologist should review all available results, but not necessarily putting in the report unless it affects the differential diagnosis or diagnosis in any way 4 Prothrombin time must be assessed on every potential leukemia patient, the best and easiest way to rule out DIC in the patient not yet obviously bleeding. Not "when available" 9/1/ :01 AM 8/31/ :36 PM 8/31/2015 2:40 PM 8/31/ :36 AM 5 These are not needed for diagnosis. 8/31/ :10 AM 6 The critical word here is "pertinent". All of this data should not be added to the report if it does not directly relate to the diagnosis. Also, if all of the data is in readily accessible electronic medical record, the need to add it into the hematopathology report is diminished. If the patient is referred elsewhere, pertinent clinical laboratory data will likely be sent with the hematopathology report. 7 If the goal of this statement is to encourage efforts to make the diagnosis of APL, it may be more effective to be explicit. Suggestion: "To expedite the diagnosis of APL, the pathologist should review the results of chemistry assays and coagulation studies when available, and include any pertinent data in the final report." 8/30/2015 8:26 PM 8/28/2015 2:06 PM 8 STRONGLY AGREE 8/28/ :11 PM 9 Chemistry assays? way too vague. Please specify. 8/28/2015 6:57 AM 10 Not always necessary, and not all is necessary 8/27/2015 6:57 PM 32 / 99

12 11 It is not clear which studies are being referred to here and it is not clear how these impact pathologic diagnosis. The clinicians certainly need to be aware of these data independent of the pathologist. 12 If the goal of this statement is to enhance the likelihood of diagnosing APL, it would be best to be explicit that that is the issue. 13 Other than the LDH I am not sure the chemistry assays really add much to the pathology picture. I do not think the pathologist should have to add the chemistry and coagulation results on their report as they are already reported elsewhere. 14 It is hard to interpret some assays without clinical context, i.e. ferritin can be high for many reasons and may be misleading without knowing all of the clinical information. Likewise, patient may have bleeding or clotting disorder (or be on coag related medications, warfarin, heparin, etc) not disclosed to pathologist and abnormal coags could be alarming and misleading in that situation. 8/27/2015 4:53 PM 8/27/2015 4:21 PM 8/26/2015 3:40 PM 8/26/ :40 PM 15 Coagulation studies can be complicated to interpret; should not be a basic requirement for a bone marrow report 8/26/ :14 PM 16 This should be performed in collaboration with the clinician 8/26/2015 2:34 AM 17 Note that when samples are sent off to national reference labs often this is not possible and that is a shame. 8/25/ :09 AM 18 Only if pertinent. 8/25/2015 9:48 AM 19 This may be problematic if chemistry and coagulation studies are performed separate (in another laboratory) from the actual bone marrow. Reviewing and interpreting results from other laboratories is an issue unless a complete medical report with reference ranges is also included. 20 When directly provided maybe but should not be a requirement that pathology go search this out. This is a creeping workload that is unfair to put on pathology. 21 If the final diagnosis requires assessment of these markers, it would be helpful to assess chemistry assays. In general, there is minimal information gained for the majority of diagnoses hematopathologists encounters in routine practice. 8/25/2015 9:09 AM 8/25/2015 3:36 AM 8/24/2015 5:02 PM 22 Pathology report should integrate AP and CP elements. 8/24/2015 3:52 PM 23 There is no need to duplicate information that is already in the EMR unless it is directly used to refine a diagnosis 8/24/2015 3:47 PM 24 It is not practical for the pathologist to review such a wide range of laboratory tests, especially as she/he might not often had ready access to them. This is best considered part of the clinical and laboratory correlation that needs to be undertaken by the treating clinician(s). 25 Chemistry: Specifically LDH, uric acid,? Coag: Specifically PT/inr, PTT, Fib, D-Dimer Emphasis needed for recommendation of standard "DIC coag panel" tests being performed, especially with AML's? Since the potential for DIC represents possible immediate patient risk, where the abnormal chemistry tests can be used for correlation but are not diagnostic. 8/24/2015 3:37 PM 8/24/2015 3:13 PM 26 I think we risk introducing error into the medical record 8/24/ :06 AM 27 These studies are not always available to the pathologist, especially if the marrow was performed as an outpatient. If provided and information is pertinent, this data should be included in the report. 8/20/2015 9:02 AM 28...and imaging studies if available. 8/19/2015 7:23 PM 29 The interaction with the pathologist is not important for the treatment of AML 8/19/2015 4:19 PM 30 Unfortunately Hematopathologists exist only in North America. In Israel like in Europe there is an hematology lab where all the "fluid" tests (e.g. CBC, FACS, cytogenetics etc) are performed while only histology is seen by an hematopathologist. It is up to the clinician to integrate the laboratory with the clinical data into a precise diagnosis. Personally I believe that the American model of hematopathologists should also become the standard in Europe and worldwide. This should be a formal recommendation of ASH 31 This may be challenging depending on the institution, but can be very helpful e.g. in case of B12 deficiency and other conditions that can significantly affect bone marrow pathology. 8/19/2015 3:31 PM 8/19/2015 3:26 PM 32 Not sure 8/19/2015 3:26 PM 33 Most reporting by Pathology is tissue and specimen based. Staging has not been a strategy in reporting on acute leukemia. What would a comprehensive report look like in the same manner as the synoptic report mandated by CAP for solid tumors. 34, some data can be critical for the final diagnosis. But data included without further interpretation may not be helpful, while further inteprating chemistry or coagulation data may not be in the scope of the report. Better to further specify this statement in a subset of AML or regarding specific results 8/18/2015 3:09 PM 8/18/ :01 PM 33 / 99

13 35 Should say: "The treating clinician should provide relevant chemistry assays and coagulation studies or ensure that these are readily accessible by the pathologist. The pathologist should review these results when available, and include any pertinent data in the final report." This should emphasize the need to provide the pathologist with relevant laboratory information obtained in outpatient settings. 36 Chemistry assays and coagulation studies are not so specific for making diagnosis of acute leukemia. Morphology/immunophenotyping/genetic test are enough for making diagnosis. 8/14/ :09 PM 8/12/ :49 PM 37 It is mandatory for all the samples, for all the types of leukemia? 8/12/2015 3:55 AM 38 Coagulation studies are rarely ordered and hardly ever pertinent. 8/11/ :16 AM 39 In occasional cases this may be helpful and pertinent, but going over chemistry results on every patient in the report will be time consuming with limited utility. 8/10/2015 3:26 PM 34 / 99

14 Statement 4: The pathologist should include the results of a recent or concurrent complete blood count (CBC) with leukocyte differential and peripheral smear evaluation in the final report. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Answer Choices Responses 96.52% % 7 Total 201 # Comment Date 1 Completely agree 8/31/2015 2:40 PM 2 It shouldn't be the pathologist's job but if it will make more people pay attention to the cbc and diff, probably a good idea 8/31/ :36 AM 3 Also not needed for diagnosis. 8/31/ :10 AM 4 Fully agree. 8/30/2015 8:26 PM 5 Peripheral smear review should not be required for all cases, but may be performed for some cases. 8/30/2015 6:02 PM 6 This is very vital and happens in most hematopathology practices today. 8/30/ :02 AM 7 Surely and should do it all the time 8/28/ :11 PM 8 CBC must be included 8/27/2015 6:57 PM 9 perhaps clinician or pathologist (whomever is in charge of obtaining the bone marrow specimen) should ensure a cbc is drawn for peripheral smear review along with the bone marrow specimen 10 There are some diseases (i.e. CMML) where the diagnosis can not be made without the peripheral smear results. There are other diagnoses (i.e. CML) where the patient can not be properly staged without the peripheral smear. 11 The CBC should always be reported. The differential is not always crucial, but should be reported/critical elements of the differential should be reported in the final report. This would be easiest if it is autopopulated in the report. 12 with differential and smear evaluation. Not sure that CBC data needs to be repeated in marrow report if readily available in EMR 8/27/2015 9:43 AM 8/26/2015 3:40 PM 8/26/2015 6:55 AM 8/25/2015 4:38 PM 13 The majority of cases have unremarkable morphology, or the Peripheral smear is not submitted with the sample. 8/25/ :15 PM 35 / 99

15 14 No need to repeat data that is readily available in the EHR that led to the further hematologic workup for leukemia. 8/25/2015 9:48 AM 15 Reviewing and interpreting CBC data from another laboratory can be a problem unless a complete medical report including reference ranges is included. 8/25/2015 9:09 AM 16 This is based on availability of the peripheral blood smear to review. 8/24/2015 7:49 PM 17 Pictures are nice too 8/24/2015 3:52 PM 18 Duplicates the EMR for hospital based pathologists. Include only if directly contributes to the diagnosis. 8/24/2015 3:47 PM 19 If these results are available, they should be included. 8/24/2015 3:37 PM 20 The pathologist himself should review the smear not just look at results and also result prior blood counts for trends 8/20/ :11 AM 21 If information is available. 8/20/2015 9:02 AM 22 This is the clinician's task not the pathologist 8/20/2015 4:01 AM 23 Strengthen the statement, by requiring concurrent examination and count by the pathologist. 8/19/2015 7:23 PM 24 All should be made by the clinical hematologist by himself 8/19/2015 4:19 PM 25 This is essential 8/17/ :28 AM 26 Should say: "The pathologist should include the results of a recent or concurrent complete blood count (CBC) with leukocyte differential and peripheral smear evaluation in the final report or on a contemporary separate report." This is needed to avoid repeat unnecessary charges if a peripheral blood examination has been issued a few hours or days before the bone marrow is performed. 27 In the outpatient setting, the CBC is sometimes performed at a physician office lab, in that case the CBC and differential plus a peripheral blood smear should be sent by the referring physician to the pathologist 8/14/ :09 PM 8/12/2015 8:12 PM 28 CBC and smear should be done at the time of marrow biopsy for more precise correlation. 8/11/2015 6:37 PM 29 The clinician should order a CBC with differential on all patients undergoing bone marrow examination! 8/11/ :16 AM 30 CBC data and peripheral smear morphology for the preceding year is desirable, if available 8/10/2015 4:52 PM 31 If we just did a peripheral smear review which led to the bone marrow, we will reference the recent peripheral smear review. Typically, in acute leukemia, we get another CBC the day of the bone marrow especially if the counts are changing rapidly. 8/10/2015 4:07 PM 36 / 99

16 Statement 5: The treating clinician or pathologist should obtain a fresh bone marrow aspirate for all patients suspected of acute leukemia, a portion of which should be used to make bone marrow aspirate smears which should be evaluated by the pathologist.note: If bone marrow aspirate material is inadequate or if there is compelling clinical reason to avoid bone marrow examination, blood and ancillary studies may be used for diagnosis if sufficient blasts are present. If a bone marrow aspirate is unattainable, touch imprint preparations of a core biopsy should be prepared and evaluated and an additional core biopsy may be submitted for ancillary studies. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Answer Choices Responses 94.24% % 11 Total 191 # Comment Date 1 At least in Europe the bone marrow aspirate smears are frequently evaluted by an hematologist. 8/31/2015 3:58 PM 2 If a bone marrow aspirate is unattainable, technical manipulation of the freshly obtained (non-fixed) core biopsy in the lab can lead to successfully getting viable cells for the essential additional ancillary tests, as needed for the case as evaluated by the pathologist/clinician at the time (low cellular yield but could be adequate for essential additional test). 8/31/2015 2:56 PM 37 / 99

17 3 There should NEVER be a reason to avoid bone marrow examination, Never. Too many patients have been hurt by doctors who think peripheral blasts are enough to diagnose and follow. Of course, a unaspirable marrow should be biopsied, but otherwise aspirate is adequate and avoids the risk of deep bleeding from biopsy. Aspiration should always be obtained by someone expert in assuring spicules are adequate. These guidelines suggest a pathologist is always available, everywhere, 24/7 to read emergency specimens and that is not true. A patient must be able to get anti-leukemia chemotherapy started within hours of presentation if the features of his disease warrant it, so his life is not put at risk by doctors waiting for a pathologist. Spicules can be stained and read by on-call personnel 4 Would emphasize the exception: "if there is compelling clinical reason to avoid bone marrow examination, blood and ancillary studies may be used for diagnosis if sufficient blasts are present." Would be nice to have guidelines for older adults that may not need mandatory bone marrow evaluation if treatment options are limited. 8/31/ :46 AM 8/31/ :06 AM 5 initial studies if appropriate should be done on blood if marrow examination would be delayed for example weekend 8/31/ :02 AM 6 If a bone marrow aspirate is unattainable, an additional core biopsy may be obtained fresh (not fixed) for tissue mincing and cell release (cell disaggregation) that could be used for morphologic, flow cytometric, cytogenetic and/or other ancillary studies. 8/31/ :23 AM 7 Fully agree. This should be standard of care. 8/30/2015 8:40 PM 8 In the note, "unattainable" should be changed to "unobtainable" 8/28/2015 4:42 PM 9 If aspirate is not possible because of a fibrotic or packed marrow a core biopsy in tissue culture media may be helpful for preparation for flow cytometry and cytogenetics. 8/26/2015 4:00 PM 10 Smears must be evaluated by the pathologist, and NOT by treating clinician. 8/26/2015 3:51 PM 11 A core biopsy should be performed on all patients at initial diagnosis unless there is a contraindication or technical difficulty obtaining one. The core and the aspirate provide complementary information. I think it is very important that the same person who is looking at the biopsy (the pathologist) should at least have access to the aspirate. I have seen several cases where the patient was misdiagnosed because the hematologist reviewed the aspirate (often without doing a formal 500 cell count differential) and the pathologist reviewed the core. The pieces need to be reviewed together. It is also important to stress that a formal differential must be performed on the aspirate unless spicules can not be obtained. 8/26/2015 3:49 PM 12 "Sufficient blasts" is not clear. 8/26/2015 2:39 AM 13 The drawback to use of peripheral blood for initial immunophenotyping and genetic studies is the need to delay onset of treatment until it is known that test results are informative. 8/25/ :22 PM 14 If a dry "tap" is encountered it is also possible to send an additional core biopsy for flow and cytogenetics etc. 8/25/ :32 AM 15 I think is better to submitt a tube of peripheral blood at the same time the bone marrow is submitted. Sometimes the bone marrow aspirate is not adequate for review (acellular [due to fibrotic marrow], markedly hemodiluted, etc.) and is better to save time to evaluate the peripheral blood instead of marrow. So highly recommend sending the blood the same time. 8/24/2015 7:56 PM 16 Strongly agree 8/24/2015 5:11 PM 17 Without bone marrow aspirate or biopsy, diagnosis only possible if WHO recognized recurrent genetic abnormalities are present. 18 I think that there are many cases in which the blood is completely adequate to diagnose and characterize an acute leukemia 8/24/2015 3:18 PM 8/24/ :08 AM 19 First sentence needs a period at the end of the statement. 8/20/2015 3:09 PM 20 If a core biopsy is performed before the aspirate, touch imprints should always be made before depositing the biopsy into formalin. 21 I strongly agree. Many diagnoses are made from peripheral blood, and that tissue may not supply adequate material for full assessment. 22 In pediatrics we would be satisfied with peripheral blood with adequate blasts and studies of cytogenetics, molecular data and flow cytometry without doing a core biopsy 23 At initial diagnosis a core biopsy should be performed as the degree of marrow infiltration may be misleading via aspirate. 8/20/2015 2:44 PM 8/20/2015 1:24 PM 8/20/ :15 AM 8/20/ :28 AM 24 Imprints should be made on all biopsy specimens. Cost is minimal and information gained can be essential. 8/19/2015 7:31 PM 25 I am not aware of evidence that special studies (especially flow cytometry) are done more accurately on touch imprint preparations than on peripheral blood if substantial numbers of blasts are present in the peripheral blood. 8/19/2015 5:59 PM 38 / 99

18 26 Bone marrow aspirate smears either at disgnosis or at the time of response evaluation must be performed by the hematologist 8/19/2015 4:22 PM 27 I think that clinicians generally underestimate the value of touch preps, and I am pleased that this is in the draft. 8/19/ :11 AM 28 also for flow cytometry 8/17/2015 6:14 PM 29 Bone marrow aspirate and biopsy for initial diagnosis, correct? Oftentimes due to difficulty with collections the aspirates can be suboptimal and that may impede diagnosis. 8/17/ :35 AM 30 Performing an aspirate and biopsy as initial work up will help obviate repeat sampling needs with inadequate aspirates 8/17/ :22 AM 31 Since bone marrow acquisition techniques can cause discomfort to an already confused patient ancillary techniques on blood samples could be done. 32 Should also mention obtaining a blood sample for morphology review. Blood provides morphology clues to differentiation, presence of dysplasia, and blast count may determine diagnosis. Believe it or not, we still see times when a marrow is done but a concurrent blood sample is not drawn. 33 It is important to remember that for inaspirable marrows, core biopsies may be obtained and transported to the laboratory in a medium such as RPMI supplemented with 10% fetal bovine serum, to enable flow cytometric, cytogenetic, and/or FISH evaluation of fresh cells. 8/11/2015 1:43 PM 8/10/2015 5:49 PM 8/10/2015 5:10 PM 34 "unattainable" should be "unobtainable" 8/10/2015 4:17 PM 39 / 99

19 Statement 6: The pathologist may evaluate an adequate bone marrow trephine core biopsy, bone marrow trephine touch preparations, and/or marrow clots, in conjunction with bone marrow aspirates. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Answer Choices Responses 81.77% % 35 Total 192 # Comment Date 1 I believe a core biopsy is complementary at diagnosis and would make this is "should". 8/31/2015 8:32 PM 2 Instead of "may", the pathologist "should" evaluate an adequate bone marrow trephine core biopsy, bone marrow trephine touch preps and/or marrow clots, in conjunction with bone marrow aspirates. Aspirate smears alone do not provide complete information for a bone marrow biopsy evaluation. To move towards gene expression/mutation analysis without having complete basic bone marrow biopsy evaluation does not seem to make sense. 8/31/2015 2:56 PM 3 A core biopsy should be evaluated. 8/31/ :51 AM 4 In some hospitals, cytology (BM aspirates) and pathology (trephine biopsy) are treated by different departments simultaneously, with interaction amongst departments only done for dubious cases prior to submitting the final report. This serves as a double, independent validation of the diagnostic, and has been a successful model in our center. 5 If provided, the pathologist should evlauate the biopsy. The hematologist should obtain a biopsy in addition to a smear on a patient with a new question of hematologic malignancy. 8/31/ :43 AM 8/31/ :29 AM 6 The pathologist SHOULD evaluate... 8/31/ :23 AM 7 Bone marrow biopsy should be mandatory. Clot preparations should be avoided. 8/31/ :16 AM 8 Bone marrow core biopsy should be evaluated with aspirate. Aspirate may be hemodiluted and underestimate the blast percentage. 9 In my world, the "may" above is "always should". I understand that in some settings, trephine biopsies are not performed in conjunction with aspirates. Being pragmatic, this is probably adequate in most situations. However, if you obtain a dry tap or near dry tap on an aspirate, you really don't know if there is a physical property (e.g. fibrosis) causing the dry tap or if it is a technical issue with the biopsy. I would suggest something stronger than "may", I can see the difficulty, however. 8/31/ :15 AM 8/30/2015 8:40 PM 10 Pathologist should compare the aspirate with core and make a statement in the repoirt33 8/28/ :19 PM 40 / 99

20 11 Bone marrow histology should be required. The current statement perpetuates the idea that myeloid neoplasms are aspirate only diagnoses which is wrong. At the time of the initial assessment, one does not know that the case represents garden variety AML. Could APMF, high grade MDS, MDS/MPN, secondary AML e.g. blast phase of an MPN patient. 12 It appears to be good practice to always evaluate histologic material. In advance, it cannot be known whether the blood/aspirate material will be adequate for diagnosis and focal lesions or importance can be missed without histologic material. 8/28/2015 7:41 AM 8/27/2015 4:56 PM 13 although I lean towards this being a should in terms of clot/biopsy 8/27/2015 9:44 AM 14 The pathologist SHOULD evaluate an adequate bone marrow trephine core biopsy, etc. 8/26/2015 3:51 PM 15 I think "may" is not strong enough. The pathologist "should" evaluate an adequate core, etc unless it cannot be obtained for some reason (obesity, etc). 8/26/2015 3:49 PM 16 I think they should be attempted on every case. 8/26/2015 1:38 PM 17 SHOULD, not may! BM asiprate and biopsy should both be evaluated by the pathologist in all circumstances except when clinically unable to obtain one of the specimen types. It is dangerous to evaluate one without the other (aspirate may be hemodilute while biopsy may have fibrosis and increased blasts or biopsy may be of poor quality and many blasts seen on aspirate, etc) 8/26/ :40 PM 18 pathologist should evaluate all aspects of specimen submitted 8/26/ :15 PM 19 There have been enough cases in my career where the biopsy contained critical findings not present in the aspirate that I think a biopsy "should" be evaluated in nearly all cases. The exception might be some routine cases of pediatric ALL. 8/26/2015 7:19 AM 20 the pathologist should... 8/26/2015 2:39 AM 21 Biopsy can provide important confirmation of cellularity and cells for immunohistochemistry if needed. 8/25/ :22 PM 22 Trying to make touch imprints of biopsy samples only ruins the biopsy by introducing artifacts. 8/25/ :18 PM 23 I have seen quite a few cases where blast counts are much lower in a dilute aspirate than in a core biopsy. This usually occurs when the marrow is difficult to aspirate and dilute which is not that uncommon with acute leukemia. So I would prefer "when possible should"... Additionally IHC studies can give additional information important to classification in some cases even though the CMS considers it "duplicate testing". That is a shame because sometimes it is required for precise diagnosis and classification. A statement acknowledging this would be helpful in such disputed and perhaps be further evidence of for the CMS to reconsider this policy. 24 The pathologist SHOULD evaluate bone marrow trephine bore biopsy, touch preparations, and/or marrow clots in conjunction with the aspirates. Separate parts of a bone marrow aspirates/biopsy should not be evaluated in isolation. 25 Statement 6 above should be change: the word "may" should be replaced with "must". In my opinion and experience (20+ years) and aspirate alone can be quite misleading and a core biopsy should always be obtained. Additionally, the core biopsy provides information that is NOT available from an aspirate smear. 8/25/ :32 AM 8/25/2015 9:17 AM 8/24/2015 6:03 PM 26 The pathologist MUST evaluate the biopsy, if collected, with the aspirate. 8/24/2015 3:53 PM 27 The statement should read 'should' instead of 'may.' Acute leukemia is such an important diagnosis, that it would seem silly to go through the process of obtaining a marrow aspirate, and then not attempt to obtain and review a core and/or clot as well. Some types of acute leukemia (such as acute megakaryoblastic leukemia) are difficult to diagnosis with a quality core. 28 Core biopsy should be included whenever possible, especially if there is a "dry tap". It may be the best specimen for evaluation of myelofibrosis or metastatic malignancy. 8/24/2015 3:41 PM 8/24/2015 3:39 PM 29 I would recommend changing wording to, "The pathologist should evaluate..." 8/24/ :26 AM 30 I gather that there was concern that every patient with acute leukemia does not need to have a bone marrow biopsy to diagnose acute leukemia if there is an adequate aspirate and blood blasts.. On the other hand as noted below, the availability of a biopsy may be able to yield other information about the immunophenotype and other molecular aspects. 8/20/2015 2:44 PM 31 Pathologist MUST review these if they have been done 8/20/ :15 AM 32 Noneteless, a bone marrow biopsy should not be an indispensable requirement for a proper AML diagnosis 8/20/2015 5:06 AM 33 This is the clinician's responsibility 8/20/2015 4:04 AM 41 / 99