Acute Myelogenous Leukemia (AML) is a cancer of the white blood cells. It is characterized by the rapid proliferation of abnormal, immature myelocytes, known as myeloblasts, in the bone marrow. This accumulation of blasts in the marrow prevents the formation of healthy red blood cells, white blood cells, and/or platelets. Normal myeloblasts develop into neutrophils, basophils, and eosinophils, which are all white blood cells that fight infection. In AML, the leukemic myeloblasts do not fully develop and are unable to fight infection. The symptoms of AML result from a drop in red blood cell, platelet, and normal white blood cell counts caused by the replacement of normal bone marrow with leukemic cells.

Certain prognostic indicators are associated with poorer outcomes. These include advanced age (50+ years of age), AML arising from MDS or secondary / therapy-related AML, and certain genetic mutations that are described in greater detail later in this manual.

Question 3: Specify the AML classification

Indicate the disease classification at diagnosis

Report the most specific entity that applies to the recipient. For example, if the recipient was classified using both cytogenetic data and the M5 FAB classification, the more specific cytogenetic data should be reported for classification purposes.

Question 4: Did AML transform from MDS or MPN?

AML often evolves from MDS or MPN. This transformation is typically distinguished by the percentage of blasts in the bone marrow

AML that transforms from MDS or MPN has a lower survival prognosis because of the association with unfavorable cytogenetic abnormalities.

AML can also evolve from Juvenile Myelomonocytic Leukemia (JMML). JMML is a rare form of chronic leukemia that affects young children, usually before the age of five. JMML results from DNA mutations in cells called monocytes. Normal monocytes attack invading microorganisms and assist lymphocytes in carrying out immune functions. Abnormal monocytes in JMML accumulate in the bone marrow and interfere with the production of normal white blood cells, red blood cells, and platelets.

If AML transformed from MDS or MPN (including JMML), check “Yes” and complete both the AML and MDS / MPN disease classification sections of this form. If AML did not transform from MDS or MPS, check “No.”

If MDS / MPN is suspected, but not confirmed by documented laboratory or pathologic findings, or if there is documentation of MDS / MPN concurrent with AML, check “No.”

Question 5: Is the disease (AML) therapy related?

Agents such as radiation or systemic therapy used to treat other diseases (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, or breast cancer) can damage the marrow and lead to a secondary malignancy such as AML. If the diagnosis of AML is therapy-related, check “Yes.”

If the diagnosis of AML is not therapy-related, check “No.”

  • If AML was preceded by therapy-related MDS, check “No.”
  • If the recipient developed AML after an environmental exposure (e.g., exposure to benzene), check “No.”

If it is unknown whether or not the diagnosis of AML was therapy-related, check “Unknown.”

Question 6: Did the recipient have a predisposing condition?

A predisposing condition is a condition that contributes to the susceptibility of developing leukemia. Therefore, diagnosis of the condition increases the likelihood that the recipient will develop leukemia. If the recipient has a documented history of a predisposing condition, check “Yes” and continue with question 7. If there is no history of a predisposing condition or if predisposition is unknown, indicate “No” or “Unknown” and continue with question 9.

Question 7-8: Specify condition:

Bloom syndrome is an autosomal recessive genetic disorder characterized by excessive chromosome breakage and corresponding rearrangements, proportional dwarfism, and sun sensitivity. The chromosomal instability seen in Bloom syndrome is generally assumed to be responsible for these individuals’ predisposition to malignancy.

Down syndrome is also a chromosomal disorder (trisomy 21). It is characterized by an additional chromosome 21. Down syndrome patients exhibit a particular set of facial characteristics, growth deficiency, and cognitive impairment. Although Down syndrome patients have a reduced risk of developing many common malignancies, they have an increased risk of developing leukemia.

Fanconi anemia is a rare genetic blood disorder that prevents the body from producing a sufficient number of new blood cells to function properly. Abnormal blood cells may also be produced. These patients are short in stature, exhibit skeletal anomalies, and have an increased risk of developing solid tumors and leukemias.

Dyskaratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, involves progressive bone marrow failure. Patients with DKC experience skin hyperpigmentation, nail dystrophy, and oral leukoplakia (a white patch / plaque that cannot be rubbed off).

Indicate the recipient’s predisposing condition prior to the diagnosis of leukemia. If the recipient has a documented history of a predisposing condition but it is not listed as an option in question 7, select “Other condition” and specify the condition in question 8.

Question 9: Were cytogenetics tested (karyotyping or FISH)? (at diagnosis)

Cytogenetic analysis is the study of chromosomes. Cytogenetic assessment involves testing blood or bone marrow for the presence of a known chromosomal abnormality which reflects the recipient’s disease. Testing methods you may see include conventional chromosome analysis (karyotyping) or fluorescence in situ hybridization (FISH). For more information about cytogenetic testing and terminology, see Appendix C, Cytogenetic Assessments.

Karyotyping is performed by culturing cells (growing cells under controlled conditions) until they reach the dividing phase. Techniques are then performed to visualize the chromosomes during cell division so that various bands and reconfigurations can be seen. Banding pattern differentiation and chromosomal reconfiguration demonstrate evidence of disease.

FISH is a sensitive technique that assesses a large number of cells. This technique uses special probes that recognize and bind to fragments of DNA. These probes are mixed with cells from the recipient’s blood or bone marrow. A fluorescent “tag” is then used to visualize the binding of the probe to the diseased cells.

Table 3. Examples of AML Cytogenetic Findings Categorized by Prognosis

Favorable Intermediate Poor
t(15;17)
t(8;21)
inv(16) or t(16;16)
Normal
+8
t(9;11)
All other abnormalities
≥ 3 abnormalities
5- or 5q-
7- or 7q-
t(9;22)

Indicate whether cytogenetic studies were performed at diagnosis. Do not report any testing performed after treatment for AML has started. If cytogenetic studies were obtained at diagnosis, check “Yes” and go to question 10. If cytogenetic studies were not obtained at this time point or it is not known whether chromosome studies were performed, indicate “No” or “Unknown” respectively and go to question 23.

Question 10-11: Were cytogenetics tested via FISH?

If FISH studies were performed at diagnosis (see note box above question 9), report “Yes” for question 10 and indicate whether clonal abnormalities were detected in question 11. Do not report any testing performed after treatment for AML has started. If FISH studies were not performed at this time point, report “No” for question 10 and go to question 16. Examples of this include: no FISH study performed or FISH sample was inadequate.

Report chromosomal microarrays / chromosomal genomic arrays as FISH assessments.

Question 12-15: Specify cytogenetic abnormalities (FISH)

Report the International System for Human Cytogenetic Nomenclature (ISCN) compatible string if applicable in question 12, then continue with question 13.

Specify the number of abnormalities detected by FISH at diagnosis (see note box above question 9) in question 13. After indicating the number of abnormalities in question 13, select all abnormalities detected in questions 14-15.

If a clonal abnormality is detected, but not listed as an option in question 15, select “Other abnormality” and specify the abnormality in question 15. If multiple “Other abnormalities” were detected, report “see attachment” in question 15 and attach the final report(s) for any other abnormalities detected. For further instructions on how to attach documents in FormsNet3SM, refer to the Training Guide.

Question 16-17: Were cytogenetics tested via karyotyping?

If karyotyping was performed at diagnosis (see note box above question 9), report “Yes” for question 16 and indicate whether clonal abnormalities were detected in question 17. Do not report any testing performed after treatment for AML has started. If karyotyping was not performed at this time point, indicate “No” and go to question 22. Examples of this include: karyotyping was not performed or karyotyping sample was inadequate.

Question 18-21: Specify cytogenetic abnormalities (karyotyping)

Report the International System for Human Cytogenetic Nomenclature (ISCN) compatible string if applicable in question 18, then continue with question 19.

Report the number of abnormalities detected by karyotyping at diagnosis (see note box above question 9) in question 19. After indicating the number of abnormalities in question 19, select all abnormalities detected in questions 20-21.

If a clonal abnormality is detected, but not listed as an option in question 20, select “Other abnormality” and specify the abnormality in question 21. If multiple “Other abnormalities” were detected, report “see attachment” in question 21 and attach the final report(s) for any other abnormalities detected. For further instructions on how to attach documents in FormsNet3SM, refer to the Training Guide.

Question 22: Was documentation submitted to the CIBMTR?

IIndicate if a karyotyping or FISH testing report is attached to support the cytogenetic findings reported in questions 9-21. For further instructions on how to attach documents in FormsNet3SM, refer to the Training Guide.

Question 23: Were tests for molecular markers performed (e.g., PCR, NGS)? (at diagnosis)

Molecular markers for disease refer to specific genetic sequences which are believed to be associated with the recipient’s primary disease. Testing for these sequences is often performed using PCR based methods; however, lower sensitivity testing, including FISH, may also be used to detect molecular markers. Once a marker has been identified, these methods can be repeated to detect minimal residual disease (MRD) in the recipient’s blood, marrow, or tissue. Molecular assessments include polymerase chain reaction (PCR) amplification to detect single specific disease markers; however, molecular methods are evolving and now include Sanger sequencing, and next generation sequencing (e.g., Illumina, Roche 454, Proton / PGM, SOLiD).

If testing for molecular markers was performed at diagnosis (see note box above question 9), report “Yes” and go to question 24.

If molecular marker testing was not performed at diagnosis or it is not known if testing was done, report “No” or “Unknown” respectively and go to question 36.

Question 24-35: Specify results

For each molecular marker in questions 24-33, report whether testing was “Positive,” “Negative,” or “Not done” at diagnosis (see note box above question 9). If tests identified a molecular marker other than those listed in questions 24-33, report the result in question 34 and specify the marker in question 35.

If multiple “Other molecular marker[s]” were tested, report one instance (i.e., copy) of question 34-35 for each “Other molecular marker” tested. If greater than 3 “Other molecular marker[s]” were tested, do the following::

  • report one instance of question 34-35; and
  • report “Positive” if any of the “Other molecular marker[s]” were positive, otherwise, report “Negative;” and
  • report “see attachment” in question 35; and
  • attach any / all reports documenting the results of testing for “Other molecular marker[s].”

If CEBPA is reported as “Positive” (question 24) question 25 must be completed. If the lab report does not specify whether the detected marker was biallelic / homozygous or monoallelic / heterozygous, confirm with the laboratory whether this information can be determined prior to reporting “Unknown.”

If FLT3-ITD is reported as “Positive” (question 27) questions 28 and 29 must be completed. If the allelic ratio is known, report “Known” for question 28 and report the value in question 29. If the lab report does not specify the allelic ratio, confirm with the laboratory whether this information can be determined prior to reporting “Unknown.”

Table 4. Common Molecular Markers Associated with AML

Molecular Abnormality Characteristics
CEBPA CEBPA, aka CCAAT/enhancer binding protein α, is a transcription factor required for the differentiation of granulocytes. Numerous CEBPA mutations have been identified in relation to AML, with the majority of patients displaying biallelic mutations ultimately resulting in the down regulation of gene activity. Decreased gene activity results in decreased differentiation potential for immature granulocytes. An estimated 7-15% of AML patients have CEBPA mutations and CEBPA mutations are generally found in M1 and M2 subtypes in conjunction with intermediate-risk cytogenetics. Studies show an association with more favorable outcomes.1
FLT3-D835 point mutation FLT3 encodes a receptor tyrosine kinase. The FLT3-D835 point mutation, aka FLT3-TKD, is an activating mutation impacting tyrosine-kinase domains. FLT3 mutations are found in up to 1/3 of all AML patients. The clinical significance of TKD activation remains unclear. FLT3-D385 mutations are often found in conjunction with other mutations. Overall, FLT3-D385 is not considered a favorable or poor prognostic indicator. However, in certain combinations with other mutations, there are associations with both improved and diminished survival.23
FLT3-ITD mutation FLT3 encodes a receptor tyrosine kinase. The FLT3-ITD (internal tandem duplication) interferes with certain down regulation functions within receptor tyrosine kinases, leading to activation of TK activity. FLT3 mutations are found in up to 1/3 of all AML patients. FLT3-ITD is considered a poor prognostic factor. Sorafenib (Nexavar) has been shown to initially improve disease response in FLT3-ITD-positive AML.4
IDH1 Isocitrate Dehydrogenase (IDH) is an oxidative enzyme involved in the citric acid cycle. IDH1 mutations result in incorrect catalytic activity, leading to increased levels of an oncometabolite, 2-hydroxyglutarate. The pathologic activity of IDH1 mutations is still being studied, but it has been suggested that IDH mutations may be a distinct mechanism in AML pathogenesis; research models show they may cause an accumulation of hematopoietic progenitor cells. Early research suggests IDH1 mutation may be a less favorable prognostic indicator.5
IDH2 Isocitrate Dehydrogenase (IDH) is an oxidative enzyme involved in the citric acid cycle. IDH2 is a mitochondrial homolog to IDH1. Much like IDH1 mutations, IDH2 mutations result in incorrect catalytic activity, leading to increased levels of (D)-2-hydroxyglutarate. The pathologic activity of IDH2 mutations are still being studied, but it has been suggested that IDH mutations may be a distinct mechanism in AML pathogenesis; research models show they may cause an accumulation of hematopoietic progenitor cells. Early research suggests IDH2 mutation may be a more favorable prognostic indicator, unlike IDH1 mutation, though there may be differences based on where the IDH2 mutation occurs in gene.6
KIT KIT encodes a receptor tyrosine kinase. The KIT mutations at exons 8 and 17 are associated with activation of encoded proteins, resulting in activation impacting tyrosine-kinase domains. Patients with t(8;21) and inv(16) cytogenetics are frequently screened for KIT mutations, which adversely affect prognosis in these patients.7
NPM1 NPM1 encodes a protein responsible for multiple cellular functions, including the regulation of the ARF-p53 tumor suppressor pathway. Mutations in NPM1 result in gene over-expression and subsequent inactivation of ARF-p53 tumor suppression pathway. NPM1 mutations are one of the most common molecular markers seen in AML and are associated with improved survival.8
Other molecular marker Assessments for other molecular markers known or believed to be associated with AML may be performed. If these studies are performed, indicate “positive” or “negative” and specify the marker in question 56.

1 Lin L, Chen C, Lin D, Tsay W, Tang J, Yeh Y, Shen H, Su F, Yao M, Huang S, Tien H. (2005). Characterization of CEBPA Mutations in Acute Myeloid Leukemia: Most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells. Clin Cancer Res, 11, 1372-9.

2 Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE. (2007). FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 international tandem duplications in patient with acute myeloid leukemia. Blood, 110, 1262-70.

3 Whitman SP, Ruppert AS, Radmacher, MD, et al. (2008). FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications. Blood, 111, 1552-59.

4 Man CH, Fung TK, Ho C, et al. (2011). Sorafenib treatment of FLT-ITD+ acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent non-responsiveness associated with the emergence of a D835 mutation. Blood, 119 (22), 5133-43.

5 Marucci G, Maharry K, Wu YZ, et al. (2010). IDH1 and IDH2 Gene Mutations Identify Novel Molecular Subsets Within De Novo Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study. J Clin Oncol, 28(14), 2348-55.

6 Green CL, Evans CM, Zhao L, et al. (2011).The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood, 118(2), 409-12.

7 Döhner K, Döhner H. (2008).Molecular characterization of acute myeloid leukemia. Haematologica, 93(7), 976-82.

8 Varhaak RGW, Goudswaard CS, van Putten W, et al. (2005).Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood, 106(12), 3747-54.

Question 36: Were cytogenetics tested (karyotyping or FISH)? (between diagnosis and last evaluation)

See question 9 for a description of cytogenetic tests. Indicate whether cytogenetic studies were performed between diagnosis and the last evaluation prior to infusion (see note above question 9). If cytogenetic studies were obtained during this time, check “Yes” and go to question 37. If cytogenetic studies were not obtained at this time point or it is not known whether chromosome studies were performed, indicate “No” or “Unknown” respectively and go to question 50.

Question 37-38: Were cytogenetics tested via FISH?

If FISH studies were performed between diagnosis and the last evaluation prior to infusion (see note box above question 9), report “Yes” for question 37 and indicate whether clonal abnormalities were detected in question 38. If multiple FISH assessments were performed, report “Abnormalities Identified” if any testing showed clonal abnormalities during this period. If FISH studies were not performed during this period, report “No” for question 37 and go to question 43. Examples of this include: no FISH study performed or all FISH samples were inadequate.

Report chromosomal microarrays / chromosomal genomic arrays as FISH assessments.

Question 39-42: Specify cytogenetic abnormalities (FISH)

Report the International System for Human Cytogenetic Nomenclature (ISCN) compatible string if applicable in question 39, then continue with question 40.

Report the number of abnormalities detected by FISH between diagnosis and the last evaluation prior to infusion (see note box above question 9) in question 40. If FISH studies showed different clonal abnormalities during this time, report the total number of clonal abnormalities detected. After indicating the number of clonal abnormalities in question 40, select all clonal abnormalities detected during this period in questions 41-42. This includes all clonal abnormalities detected any FISH assessment performed during this period.

If a clonal abnormality is detected, but not listed as an option in question 41, select “Other abnormality” and specify the abnormality in question 42. If multiple “Other abnormalities” were detected, report “see attachment” in question 42 and attach the final report(s) for any other abnormalities detected. For further instructions on how to attach documents in FormsNet3SM, refer to the Training Guide.

Question 43-44: Were cytogenetics tested via karyotyping?

If karyotyping was performed between diagnosis and the last evaluation prior to infusion (see note box above question 9), report “Yes” for question 43 and indicate whether clonal abnormalities were detected in question 44. If multiple karyotypes were performed, report “Abnormalities Identified” if any testing showed clonal abnormalities during this period. If karyotyping was not performed during this period, report “No” for question 43 and go to question 49. Examples of this include: no karyotyping performed or all karyotype samples were inadequate.

Question 45-48: Specify cytogenetic abnormalities (karyotyping)

Report the International System for Human Cytogenetic Nomenclature (ISCN) compatible string if applicable in question 45, then continue with question 46.

Report the number of abnormalities detected by karyotyping between diagnosis and the last evaluation prior to infusion (see note box above question 9) in question 46. If karyotype studies showed different clonal abnormalities during this time, report the total number of clonal abnormalities detected. After indicating the number of clonal abnormalities in question 46, select all clonal abnormalities detected during this period in questions 47-48. This includes all clonal abnormalities detected any karyotype performed during this period.

If a clonal abnormality is detected, but not listed as an option in question 47, select “Other abnormality” and specify the abnormality in question 48. If multiple “Other abnormalities” were detected, report “see attachment” in question 48 and attach the final report(s) for any other abnormalities detected. For further instructions on how to attach documents in FormsNet3SM, refer to the Training Guide.

Question 49: Was documentation submitted to the CIBMTR?

Indicate if a karyotyping or FISH testing report is attached to support the cytogenetic findings reported in questions 36-48. For further instructions on how to attach documents in FormsNet3SM, refer to the Training Guide.

Question 50: Were tests for molecular markers performed (e.g., PCR, NGS)? (between diagnosis and last evaluation)

See question 21 for a description of testing for molecular markers. Indicate whether testing for molecular markers was performed between diagnosis and the last evaluation prior to infusion (see note above question 9). If testing for molecular markers was performed during this time, check “Yes” and go to question 51. If cytogenetic studies were not obtained during this period or it is not known whether testing for molecular markers was performed, indicate “No” or “Unknown” and go to question 63.

Question 51-62: Specify results

For each molecular marker in questions 51-60, report whether testing was “Positive,” “Negative,” or “Not done” between diagnosis and the last evaluation prior to infusion (see note box above question 9). If tests identified a molecular marker other than those listed in questions 51-60, report the result in question 61 and specify the marker in question 62.

If multiple “Other molecular marker[s]” were tested, report one instance (i.e., copy) of question 61-62 for each “Other molecular marker” tested. If greater than 3 “Other molecular marker[s]” were tested, do the following:

  • report one instance of question 61-62; and
  • report “Positive” if any of the “Other molecular marker[s]” were positive, otherwise, report “Negative;” and
  • report “see attachment” in question 62; and
  • attach any / all reports documenting the results of testing for “Other molecular marker[s].”

If CEBPA is reported as “Positive” (question 51) question 52 must be completed. If the lab report does not specify whether the detected marker was biallelic / homozygous or monoallelic / heterozygous, confirm with the laboratory whether this information can be determined prior to reporting “Unknown.”

If FLT3-ITD is reported as “Positive” (question 54) questions 55 and 56 must be completed. If the allelic ratio is known, report “Known” for question 55 and report the value in question 56. If the lab report does not specify the allelic ratio, confirm with the laboratory whether this information can be determined prior to reporting “Unknown.”

Question 63: Were cytogenetics tested (karyotyping or FISH)? (at last evaluation)

See question 9 for a description of cytogenetic testing. Indicate whether cytogenetic studies were performed at the last evaluation prior to infusion (see note box above question 9). If cytogenetic studies were obtained at this time point, check “Yes” and go to question 64. If cytogenetic studies were not obtained at this time point or it is not known whether chromosome studies were performed, indicate “No” or “Unknown” respectively and go to question 77.

Questions 64-65: Were cytogenetics tested via FISH?

If FISH studies were performed at the last evaluation prior to infusion (see note box above question 9), report “Yes” for question 64 and indicate whether clonal abnormalities were detected in question 65. If FISH studies were not performed at this time point, report “No” for question 64 and go to question 70. Examples of this include: no FISH study performed or FISH sample was inadequate.

Report chromosomal microarrays / chromosomal genomic arrays as FISH assessments.

Question 66-69: Specify cytogenetic abnormalities (FISH)

Report the International System for Human Cytogenetic Nomenclature (ISCN) compatible string if applicable in question 66, then continue with question 67.

Report the number of abnormalities detected by FISH at the last evaluation prior to infusion (see note box above question 9) in question 67. After indicating the number of abnormalities in question 67, select all abnormalities detected in questions 68-69.

If a clonal abnormality is detected, but not listed as an option in question 68, select “Other abnormality” and specify the abnormality in question 69. If multiple “Other abnormalities” were detected, report “see attachment” in question 69 and attach the final report(s) for any other abnormalities detected. For further instructions on how to attach documents in FormsNet3SM, refer to the Training Guide.

Question 70-71: Were cytogenetics tested via karyotyping?

If karyotyping was performed at the last evaluation prior to infusion (see note box above question 9), report “Yes” for question 70and indicate whether clonal abnormalities were detected in question 71. If karyotyping was not performed at this time point, indicate “No” and go to question 76. Examples of this include: karyotyping was not performed or karyotyping sample was inadequate.

Question 72-75: Specify cytogenetic abnormalities (karyotyping)

Report the International System for Human Cytogenetic Nomenclature (ISCN) compatible string if applicable in question 72, then continue with question 73.

Report the number of abnormalities detected by karyotyping at the last evaluation prior to infusion (see note box above question 9) in question 73. After indicating the number of abnormalities in question 73, select all abnormalities detected in questions 74-75.

If a clonal abnormality is detected, but not listed as an option in question 74, select “Other abnormality” and specify the abnormality in question 75. If multiple “Other abnormalities” were detected, report “see attachment” in question 75 and attach the final report(s) for any other abnormalities detected. For further instructions on how to attach documents in FormsNet3SM, refer to the Training Guide.

Question 76: Was documentation submitted to the CIBMTR?

Indicate if a karyotyping or FISH testing report is attached to support the cytogenetic findings reported in questions 63-75. For further instructions on how to attach documents in FormsNet3SM, refer to the Training Guide.

Question 77: Were tests for molecular markers performed (e.g., PCR, NGS)? (at last evaluation)

See question 21 for a description of testing for molecular markers. If testing for molecular markers was performed at the last evaluation prior to infusion (see note box above question 9), report “Yes” and go to question 78. If molecular marker testing was not performed at this time point or it is not known if testing was done, report “No” or “Unknown” respectively and go to question 90.

Question 78-89: Specify results

For each molecular marker in questions 78-87, report whether testing was “Positive,” “Negative,” or “Not done” at the last evaluation prior to infusion (see note box above question 9). If tests identified a molecular marker other than those listed in questions 78-87, report the result in question 88 and specify the marker in question 89.

If multiple “Other molecular marker[s]” were tested, report one instance (i.e., copy) of question 88-89 for each “Other molecular marker” tested. If greater than 3 “Other molecular marker[s]” were tested, do the following:

  • report one instance of question 88-89; and
  • report “Positive” if any of the “Other molecular marker[s]” were positive, otherwise, report “Negative;” and
  • report “see attachment” in question 89; and
  • attach any / all reports documenting the results of testing for “Other molecular marker[s].”

If CEBPA is reported as “Positive” (question 78) question 79 must be completed. If the lab report does not specify whether the detected marker was biallelic / homozygous or monoallelic / heterozygous, confirm with the laboratory whether this information can be determined prior to reporting “Unknown.”

If FLT3-ITD is reported as “Positive” (question 81) questions 82 and 83 must be completed. If the allelic ratio is known, report “Known” for question 82 and report the percent in question 83. If the lab report does not specify the allelic ratio, confirm with the laboratory whether this information can be determined prior to reporting “Unknown.”

Question 90: Did the recipient have central nervous system leukemia at any time prior to the start of the preparative regimen / infusion?

Central nervous system (CNS) involvement by leukemia may be detected via pathologic examination of cerebrospinal fluid or tumor tissue as well as by radiological examinations (e.g., MRI, PET/CT, MIBG, etc.). If the recipient had documented involvement of AML in the CNS, report “Yes” for question 90. If all CNS testing was negative since the time of diagnosis, report “No.” If testing for CNS involvement was not performed from the time of diagnosis to the time of HCT / cellular therapy, report “Unknown.”

Question 91: What was the disease status (based on hematologic test results)?

Indicate the disease status of AML at the last assessment prior to the start of the preparative regimen. Refer to the AML Response Criteria section of the Forms Instructions Manual for definitions of each response. For reporting purposes, consider complete remission with incomplete hematologic recovery (CRi) a complete remission (CR1, CR2, or CR3+).

If the recipient did not receive any treatment for AML from the time of diagnosis to the start of the preparative regimen / infusion, report “No treatment” and go to question 95.

If the recipient’s disease status is primary induction failure at the time of HCT / cellular therapy, go to question 95.

If the recipient’s disease status is CR / CRi at the time of HCT / cellular therapy, go to question 92.

If the recipient’s disease status is relapse at the time of HCT / cellular therapy, go to question 94.

Question 92: How many cycles of induction therapy were required to achieve 1st complete remission (CR)? (includes CRi)

Chemotherapy is initially given as induction therapy intended to bring the disease into remission. Recipients usually have one to two cycles of induction therapy; disease prognosis is considered less favorable if the patient fails to achieve remission with the first induction therapy and even poorer if patients fail two or more induction therapies.1 An example of a common induction therapy for all AML subtypes (except M3) is a combination of an anthracycline and cytarabine, commonly known as “7+3.” In this regimen, cytarabine is typically administered for seven days at a dose of 100 mg/m2/day. The anthracycline (usually daunorubicin at 45 to 60 mg/m2/day or idarubicin at 12 mg/m2/day) is generally given on the first three days the cytarabine is given.

The second phase of chemotherapy is known as consolidation therapy. The goal of consolidation therapy is to destroy any remaining leukemia cells and sustain remission. An example of a common consolidation therapy for all AML subtypes (except M3) is high-dose cytarabine, commonly referred to as “HiDAC.” In this regimen, cytarabine is typically administered at a dose exceeding 10 g/m2 per cycle.

Maintenance chemotherapy may follow consolidation therapy. Maintenance chemotherapy is given in lower doses and is intended to prolong a remission. Maintenance therapy is used less commonly for the treatment of AML than other malignancies. Treatment may also be administered for relapsed disease. Much like induction therapy, treatment for relapse is intended to bring the disease back into remission. Systemic therapeutic agents used to induce remission following relapse often differ from those used in the initial induction, since the disease is often resistant to many of the agents used earlier in the disease course and is considered high-risk with a poor prognosis. Allogeneic HCT is often considered the only potential “cure” for relapsed disease.

Indicate the number of cycles of induction therapy that were required to achieve the first CR.

1 Ravandi F, Cortes J, Faderl S, et al. (2010). Characteristics and outcome of patients with acute myeloid leukemia refractory to one cycle of high-dose cytarabine-based induction therapy. Blood, 116(26):5818-23.

Question 93: Was the recipient in remission by flow cytometry?

Question 93 will only be answered if CR has been reported for question 91. Flow cytometry assessment is a method of analyzing peripheral blood, bone marrow, or tissue preparations for multiple unique cell characteristics. Its primary clinical purpose in the setting of leukemias is to quantify blasts in the peripheral blood or bone marrow, or to identify unique cell populations through immunophenotyping. Flow cytometry assessment may also be referred to as “MRD,” or minimal residual disease, testing.

Flow cytometric remission is a treatment response in which no blasts can be detected.

If flow cytometric abnormalities associated with the recipient’s disease were identified previously, but the criteria above were met at the last evaluation prior to the start of the preparative regimen, indicate “yes.”

If flow cytometric abnormalities associated with the recipient’s disease were identified at the last evaluation prior to the start of the preparative regimen, indicate “no.”

Indicate “unknown” if flow cytometric abnormalities associated with the recipient’s disease were identified previously and no flow cytometry assessment was performed prior to the start of the preparative regimen.

Indicate “not applicable” if one of the following applies:

  • No flow cytometry assessments were performed at any time prior to the start of the preparative regimen.
  • Flow cytometric abnormalities were not identified on previous testing and no flow cytometric abnormalities were identified at the last evaluation prior to the start of the preparative regimen.

This question is optional for international centers.

Question 94: Date of most recent relapse:

Enter the date of the most recent relapse prior to the start of the preparative regimen / infusion. If reporting a pathological evaluation (e.g., bone marrow) or blood/serum assessment (e.g., CBC, peripheral blood smear), enter the date the sample was collected. If extramedullary disease was detected by radiographic examination (e.g., X-ray, CT scan, MRI scan, PET scan), enter the date the imaging took place. If the physician determines cytogenetic or molecular relapse, enter the date the sample was collected for cytogenetic or molecular evaluation. If the physician determines evidence of relapse following a clinical assessment during an office visit, report the date of assessment.

If the exact date is not known, use the process for reporting partial or unknown dates as described in General Instructions, General Guidelines for Completing Forms.

Question 95: Date assessed

Enter the date of the most recent assessment of disease status prior to the start of the preparative regimen. The date reported should be that of the most disease-specific assessment within the pre-transplant work-up period (approximately 30 days). Clinical and hematologic assessments include pathological evaluation (e.g., bone marrow biopsy), radiographic examination (e.g., X-ray, CT scan, MRI scan, PET scan), and laboratory assessment (e.g., CBC, peripheral blood smear), in addition to clinician evaluation and physical examination. Enter the date the sample was collected for pathological and laboratory evaluations; enter the date the imaging took place for radiographic assessments.

If the exact date is not known, use the process for reporting partial or unknown dates as described in General Instructions, Guidelines for Completing Forms.

Section Updates:

Question Number Date of Change Add/Remove/Modify Description Reasoning (If applicable)
. . . . .
Last modified: Dec 22, 2020

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