Curettage and Stem Cell Rescue
DATE: 11 Feb 1997 TO: MPD-SUPPORT-L FROM: R. Freeburg SUBJECT: "new" treatment for AMM/MF
STEM CELL RESCUE AFTER BONE MARROW CURETTAGE FOR THE TREATMENT OF AGNOGENIC MYELOID METAPLASIA AND RELATED MYELOPROLIFERATIVE DISORDERS by Richard Silver, Subhash Gulati, Ralph Marcove
Although I used the term "new" in the subject title (I wanted to be sure all those on "digest mode" with MF noted this study), curettage is not a new treatment for agnogenic myeloid metaplasia (also called idiopathic myelofibrosis with myeloid metaplasia). What IS more recent is the use of curettage (scraping out the fibrous tissue in the bone marrow) AND then "replacing" with stem cells that are treated (stimulated) with growth factors. The study reports that hematological remissions of up to five years were reported with curettage used years ago BEFORE genetic engineering made these growth factors (specifically granulocyte-macrophage colony stimulating factor and erythropoietin) available.
Dr. Silver sent the protocol (?) of this study to Robert Tollen for our group.The original note did not fax well, but it appears to be a new study opening up (at Cornell?) for treating AMM (included is MF secondary to PV or CML).
INTRODUCTION: A brief description of AMM and its pathogenesis (origin) is given. "Myeloid metaplasia" is used equivalently with extramedullary hematopoiesis (also hemopoiesis). This means that blood is being produced OUTSIDE of the marrow cavities where it is usually produced in the adult. In the fetus, blood IS produced in other areas - liver, spleen (although I read a recent report that wasn't sure about this one), lymph nodes --so the primitive cells still have that capability.
.........A brief aside here on terms: when we speak of "myelofibrosis," - we are referring more to the aspect of fibrous tissue filling the marrow. The terms "idiopathic MF" and "agnogenic MM" are referring usually to primary forms of the disease - not believed to be secondary to PV or CML. "Post-polycythemic myelofibrosis" or "post-polycythemic myeloid metaplasia" or "post-polycythemic splenomegaly" are secondary (PPMM, PPMF). Acute MF - related to acute megakaryoblastic leukemia - is without significant organomegaly (enlarged spleen/liver)...
In the pathogenesis of the disease, the authors mention the relationship to ineffective megakaryocytopoiesis (platelet production), along with factors (such as platelet-derived growth factor) that may stimulate fibrosis. Immune complexes are also mentioned (we have previously listed some autoimmune-MF articles) - these include positive rheumatoid factor (also implicated with reactive thrombocytosis), Coombs test, lupus anticoagulants, etc. Also briefly stated that the fibrosis seen may be a reaction to another disease - and, as such, possibly REVERSIBLE after treatment.
The clinical and laboratory features of the disease are listed. Included here is the fact that no specific chromosome abnormalities are found with the disease - unlike CML (chronic myelogenous leukemia) with its Philadelphia chromosome.
The prognosis of the disease is discussed including some poor prognosis factors found at diagnosis. With disease progression, anemia becomes more severe, spleen/liver enlarge, etc. Limited progress in treatment has been made in the last 50 years, states the article. Androgens (first reported by Silver 30 years ago) are helpful in correcting anemia. Chemotherapy, radiation, glucocorticoids have not been particularly helpful. Some do respond to erythropoietin, but the spleen may enlarge more. Bone marrow transplants - many with the disease are elderly. Splenectomy is useful in some cases; again difficult with the elderly and the liver often enlarges until failure occurs.
TREATMENT: Detail is provided into the amount of actual bone marrow present and needed for hematopoiesis; accordingly the amount to be removed by curettage from the posterior ilium (hipbone) is specific. The surgery will be conducted with epidural or light general anesthesia. The details - incision, tool used for curettage, etc., are briefly described. Recovery is several days - complications are unlikely, but include: 1) possible fracture if structural integrity of bone is weakened - this possibility can be minimized by use of crutches following the surgery 2) hemorrhage and/or infection - rare, but careful monitoring needed.
Treatment by curettage, with stimulated stem cells reinfused, is based on the hypothesis that AMM results from a defect of "marrow microenvironment." Scraping the marrow cavity may be a way of altering this faulty microenvironment so that stem cells can again implant and begin to produce blood.
MEANWHILE - stem cell collection (harvest) will occur after 6 days of pretreatment by CM-CSF (granulocyte-macrophage colony stimulating factor, market name is Leukine). A phoresis machine is used (separates the blood into its components) and collections are made every other day for 3 total collectons with 10 litres in each as tolerated. These stem cells are tested and evaluated for CD-34 cells & other factors. (The idea being that the CD-34 are the "good" stem cells that they want to return, I THINK.) Anyway, they want to end up with 300 cc of stem cells to return into the patient.
Three to five days after the final stem cell collection, the curettage and reinfusion (through a central line or peripheral IV) is accomplished. Erythropoietin and Leukine doses are continued with adjustments made according to patient response. (My words ...the idea being that the stem cells make their way to the marrow cavity - fibrous tissue has been scraped out to make room - and with the help of the stimulating growth factors, begin producing the needed blood.)
PATIENT CRITERIA AND MONITORING: Patients will be selected with documented confirmation of the diagnosis (MF secondary to PV and CML, remember, MAY be included) based on clinical and lab findings. Anemia (HGB whould be less than 10 gms%) and platelet count under 100,000 mm. Splenectomy may be performed in some cases. Progressive splenomegaly and/or hepatomegaly of any degree should be present. Careful and specific study monitoring is listed.
Dr. Silver is involved with the monitoring; Dr. Marcove does the curettage; and Dr. Gulati does the stem cell harvesting.