Q7-48: Laboratory Values at Diagnosis

Report findings at the time of diagnosis. If multiple studies were performed prior to the institution of therapy, report the values closest to the diagnosis date of the primary disease for infusion.

Questions 7-8: WBC

Indicate whether the white blood count (WBC) was “known” or “unknown” at the time of JMML diagnosis. If “known,” report the cell count and unit of measure documented on the laboratory report in question 8. If “unknown,” continue with question 9.

Questions 9-10: Hemoglobin

Indicate whether the hemoglobin was “known” or “unknown” at the time of JMML diagnosis. If “known,” report the cell count and unit of measure documented on the laboratory report in question 10. If “unknown,” continue with question 12.

Question 11: Were RBC transfused < 30 days before date of test?

Packed red blood cell transfusions temporarily increase the red blood cell count. It is important to distinguish between a recipient whose body is creating these cells and a recipient who requires transfusions to support their counts.

Indicate if red blood cells were transfused less than 30 days prior to the testing.

Questions 12-13: Platelets

Indicate whether the platelet count was “known” or “unknown” at the time of JMML diagnosis. If “known,” report the cell count and unit of measure documented on the laboratory report in question 13. If “unknown,” continue with question 15.

Question 14: Were platelets transfused < 7 days before date of test?

Platelet transfusions temporarily increase the platelet count. It is important to distinguish between a recipient whose body is creating the platelets and a recipient who requires transfusions to support their counts.

Indicate if platelets were transfused less than 7 days prior to the testing.

Questions 15-16: Monocytes

Indicate whether the percentage of monocytes in the peripheral blood was “known” or “unknown” at the time of JMML diagnosis. If “known,” report the percentage documented on the laboratory report in question 16. If “unknown,” continue with question 17.

Questions 17-18: Absolute monocyte count

Indicate whether the absolute monocyte count was “known” or “unknown” at the time of JMML diagnosis. If “known,” report the cell count and unit of measure documented on the laboratory report in question 18. If “unknown,” continue with question 19.

Questions 19-20: Blasts in blood

Indicate whether the percentage of blasts in the peripheral blood was “known” or “unknown” at the time of JMML diagnosis. If “known,” report the percentage documented on the laboratory report in question 20. If “unknown,” continue with question 21.

*If a differential was performed and there were no blasts present in the peripheral blood, the laboratory report may not display a column for blasts. In this case, it can be assumed that no blasts were present and “0” can be entered on the form.

Questions 21-23: LDH

Indicate whether LDH (lactate dehydrogenase) was “known” or “unknown” at the time of JMML diagnosis. If “known,” report the laboratory value and unit of measure documented on the laboratory report in question 22; also report the LDH upper limit of normal from the laboratory report in question 23. If “unknown,” continue with question 24.

Questions 24-25: Fetal hemoglobin (HbF)

Fetal hemoglobin is elevated in nearly 2/3 of patients with JMML and nearly all patients without monosomy 7. Greater elevation of fetal hemoglobin is associated with worse prognosis. Indicate whether fetal hemoglobin percentage was “known” or “unknown” at the time of JMML diagnosis. If “known,” report the percentage documented on the laboratory report in question 25. If “unknown,” continue with question 26.

Question 26: Was testing performed for hypersensitivity to GM-CSF?

Indicate whether testing was performed to establish if the patient was hypersensitive to GM-CSF. If “yes,” report the result as positive (hypersensitive) or negative (normosensitive) in question 27. If “no” or “unknown,” continue with question 28.

Question 28: Was the recipient’s bone marrow examined?

Indicate whether the recipient had a pathologic examination of their bone marrow. If “yes,” continue with question 29. If “no” or “unknown,” continue with question 32.

Question 29: Blasts in bone marrow

Specify the percentage of blasts in the bone marrow as documented on the pathology report. This should be taken from the aspirate differential.

Question 30: Monocytes in bone marrow

Specify the percentage of monocytes in the bone marrow as documented on the pathology report. This should be taken from the aspirate differential.

Question 31: Was documentation submitted to the CIBMTR (e.g., examination report)?

Indicate if a copy of the bone marrow pathology report is attached. Use the Log of Appended Documents (Form 2800) to attach a copy of the bone marrow pathology report. Attaching a copy of the report may prevent additional queries.

Question 32: Were cytogenetics tested (conventional or FISH)?

Cytogenetic assessment involves testing blood or bone marrow for the presence of a known chromosomal abnormality that reflects the recipient’s disease. Testing methods include conventional chromosome analysis (karyotyping) or fluorescence in situ hybridization (FISH).

Indicate if cytogenetic studies were obtained at diagnosis or prior to first therapy.

If cytogenetic studies were obtained, check “yes” and continue with question 33.

If cytogenetic studies were not obtained or it is unknown if chromosome studies were performed, indicate “no” or “unknown” and continue with question 42.

Question 33: Results of test

If cytogenetic studies identified abnormalities (any karyotype other than 46XX or 46XY), report “abnormalities identified” and continue with question 34.

If cytogenetic studies yielded no evaluable metaphases or there were no abnormalities identified, report this and continue with question 42.

Questions 34-40: Specify cytogenetic abnormalities identified at diagnosis

If question 33 indicates that abnormalities were identified, each of questions 34-39 must be answered as “yes” or “no.” Do not leave any response blank. Indicate “yes” for each cytogenetic abnormality identified at diagnosis or prior to first therapy in questions 34-39; indicate “no” for all options not identified on cytogenetic assessment at diagnosis or prior to first therapy. If at least one abnormality is best classified as “other abnormality,” specify in question 40.

Question 41: Was documentation submitted to the CIBMTR? (e.g., cytogenetic or FISH report)

Indicate if a copy of the cytogenetic or FISH report is attached. Use the Log of Appended Documents (Form 2800) to attach a copy of the cytogenetic or FISH report. Attaching a copy of the report may prevent additional queries.

Question 42: Were tests for molecular markers performed (e.g., PCR)?

Molecular assessment involves testing blood or bone marrow for the presence of known molecular markers associated with the recipient’s disease. Molecular assessment is the most sensitive test for genetic abnormalities and involves amplifying regions of cellular DNA by polymerase chain reaction (PCR), typically utilizing RNA to generate complementary DNA through reverse transcription (RT-PCR).

Indicate if molecular studies were obtained at the time the recipient was diagnosed with JMML or prior to first therapy.

If molecular studies were obtained, check “yes” and continue with question 43.

If molecular studies were not obtained or it is unknown if molecular studies were performed, indicate “no” or “unknown” and continue with question 49.

Questions 43-47: Specify abnormalities

If question 42 indicates that molecular markers were identified, then each of questions 43-47 must be answered as “positive,” “negative,” or “not done.” Do not leave any response blank.

Table 2. Common Molecular Markers Associated with JMML

Molecular Abnormality	Characteristics
BCR-ABL	BCR-ABL, aka Philadelphia chromosome, refers to the tyrosine kinase gene fusion resulting from the translocation of material from chromosome 9 (ABL) onto chromosome 22 (BCR). Molecular weight varies depending on exact location of the translocation. BCR-ABL fusion cannot be present in patients diagnosed with JMML.1
CBL	CBL genes encode for CBL proteins that are involved in protein ubiquitination, which has an effect of moderating protein tyrosine kinase signaling. Mutations to the CBL genes, particularly c-Cbl mutations, are therefore believed to be involved in a severe myeloproliferative presentation.2
K-Ras	K-Ras is one of many Ras proteins, which belong to a larger group of proteins known as GTPases. GTPases are enzymes that bind and hydrolyze GTP. Mutant K-Ras is believed to target hematopoietic progenitor cells, inducing lineage-specific malignancies.3
N-Ras	N-Ras is one of many Ras proteins, which belong to a larger group of proteins known as GTPases. GTPases are enzymes that bind and hydrolyze GTP. Mutant N-Ras is associated with increased sensitivity to GM-CSF.4
PTPN11	The PTPN11 gene encodes SHP-2, a protein tyrosine phosphatase involved with signal transduction and hematopoiesis; specifically, it relays signals from activated growth factor signals to Ras proteins, leading to cell proliferation. Mutations in the PTPN11 gene are associated with Noonan syndrome and myeloproliferative disorders, including JMML.5

¹ Wassmann B, Pfeifer H, Scheuring UJ, et al. (2004). Early prediction of response in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) treated with imatinib. Blood, 103(4):1495-1498.

² Maramatsu H, Makishima H, Jankowska A, et al. (2010). Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia. Blood, 115(10):1969-1975.

³ Zhang J, Wang J, Liu Y, et al. (2009). Oncogenic Kras-induced leukemogeneis: hematopoietic stem cells as the initial target and lineage-specific progenitors as the potential targets for final leukemic transformation. Blood, 113(6):1304-1314.

⁴ Wang J, Liu Y, Li Z, et al. (2010). Endogenous oncogenic Nras mutation promotes aberrant GM-CSF signaling in granulocytic/monocytic precursors in a murine model of chronic myelomonocytic leukemia. Blood, 116(26):5991-6002.

⁵ Kratz CP, Niemeyer CM, Castleberry RP, et al. (2005). The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood, 106(6):2183-2185.

Question 48: Was documentation submitted to the CIBMTR?

Indicate if a copy of the molecular report(s) is attached. Use the Log of Appended Documents (Form 2800) to attach a copy of the molecular report. Attaching a copy of the report may prevent additional queries.

Section Updates:

Question Number	Date of Change	Add/Remove/Modify	Description	Reasoning (If applicable)
7	4/21/2023	Modify	Clarified the instructions for the labs at diagnosis should reflect the labs closest to the date of diagnosis.	To ensure more consistent reporting, all labs for the “at diagnosis” timepoint were clarified to reflect the values obtained closest to the date of diagnosis, prior to the start of any therapy.

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