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Re: “Hemepath” post from 7/18/09

Sorry for the delay in following up with my case!  It was a good initial presentation of chronic myelogenous leukemia, chronic phase.

So, to start off with, the 5% “unclassified cells” were myeloid blasts without Auer rods.  In addition, the peripheral smear shows mostly granulocytes in varying stages of maturation.  The mature bands and neutrophils do not show toxic granulation or vacuolation or Dohle bodies.  Only 2% of the cells were basophils, but this still qualifies as an absolute basophilia.

Given these finidings, this is very suspicious for a leukemia, especially given the high serum LDH and the extreme leukocytosis. Leukemoid reaction is certainly in the differential – by pure virtue of its name, “leukemoid”, it mimics a leukemia.  However, leukemoid reaction rarely attains leukocyte counts of >100,000/ul and usually shows toxic changes in the granulocytes (vacuolation, granulation, cytoplasmic Dohle bodies).  Without any other history of infection and the man’s mild symptoms, a leukemia must be considered.  The 5% blast level would also be unlikely in a leukemoid reaction.  The low hemoglobin and platelet counts are also in favor of a process in the bone marrow that is “bullying” the other cell lineages.

These were the “unclassified cells” we counted as blasts.

The differential diagnosis could also include chronic myelomonocytic leukemia (more monocytes) a myeloproliferative neoplasm with PDGFRalpha/beta rearrangements or FGFR1 abnormalities (unlikely), or a myeloproliferative neoplasm, unclassified (or atypical CML).

I spoke with the Heme/Onc fellow who also reviewed the slide and my hematopathology attending and everyone was on the same page that this was likely CML.  A bone marrow had been done already.  The treating team started hydroxyurea, allopurinol, and hydration immediately and Gleevec (imatinib) was started the following day.

The bone marrow showed a typical picture of CML: a very hypercellular marrow with an immature shift of granulocytes, small and hypolobated megakaryocytes, and decreased erythroid precursors.  FISH for the t(9;22) BCR-ABL fusion gene showed the fusion in 98% of cells analyzed and the conventional karyotype showed the Philadelphia chromosome in all 20 cells.

The patient is doing well despite persistent mild fatigue and is due for his 3 month follow-up marrow in September.  He will also get bone marrows at 6 months and 12 months.  The most sensitive methods of follow-up, though, are by cytogenetic and molecular testing for BCR-ABL.  CML is one of the success stories in medicine, as a once fatal disease now sees 85% of patients alive and disease free at 7 years while on Gleevec.  Alternative tyrosine kinase inhibitors (e.g. dasatinib) are available should patients fail this regimen.

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I left out a few important facts that have been brought to my attention. First, it is important to rule out an accelerated and/or blast phase before signing out chronic phase CML. The 2001 WHO Classification defined the accelerated phase as:

1) Persistent or increasing WBC (>10,000/ul) and/or persistent or increasing splenomegaly unresponsive to therapy
2) Persistent thrombocytosis (>1,000,000/ul) uncontrolled by therapy
3) Persistent thrombocytopenia (<100,000/ul) unrelated to therapy
4) Clonal cytogenetic evolution occurring after the initial diagnostic karyotype
5) 20% or more basophils in the peripheral blood
6) 10-19% myeloblasts in the blood or bone marrow

Criteria 1-4 more likely evidence of transition to accelerated phase and 5&6 evidence of transition to blast phase.

According to the 2008 WHO, although suggested revisions have been recommended, these criteria are still the WHO guidelines. Evidence of accelerated phase may also include dysplasia or large clusters/sheets of megakaryocytes with fibrosis.

The blast phase may be defined as:

1) Blasts equal or are greater than 20% of the peripheral blood WBC or of the nucleated cells of the BM
2) Extramedullary blast proliferation (skin, nodal, spleen, bone, CNS…)

The blasts may be myeloblasts or lymphoblasts. There were 1% myeloblasts in the marrow of my case. We also recounted the peripheral blood and counted only 1% blasts circulating, which correlated with the marrow count. Therefore, accelerated phase or blast phase have been ruled out from a pathological standpoint.

I am checking to follow up on a question as to whether qPCR was used for detecting BCR-ABL in this patient. I assume it was done. Also, I will try to followup on the question of flow cytometry – what the maturation disruption in the CD11b/CD16 curve specifically showed.

Thanks for the follow up. Nice case.