Table of contents :

The MDS/MPD category includes myeloid disorders that have both dysplastic and proliferative features at the time of initial presentation and that are difficult to assign to either the myelodysplastic or myeloproliferative group of diseases. The WHO classification provides a less restrictive view of these diseases than do previous classification schemes that arbitrarily assigned them to either the MDS or MPD category^{ref1, ref2}. For individual patients, the clinician may view the patient in the context of whether proliferative or dysplastic manifestations predominate and treat accordingly. For cooperative groups and clinical investigators, the WHO category of MDS/MPD may allow for more focused clinical and scientific investigation of these entities that overlap 2 major disease categories. The criteria for the recognition of these disorders are detailed in the WHO monograph, but some aspects of CMML and aCML are particularly problematic and warrant some comment here. The molecular pathogenesis of MPD/MDS is poorly understood, but a subset of patients presents with translocations that disrupt and constitutively activate protein tyrosine kinases, most commonly the platelet-derived growth factor  receptor or the fibroblast growth factor receptor 1 (FGFR1)^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8}.

• chronic myelomonocytic leukemia (CMML) with eosinophilia : CMML has generated considerable controversy among a number of investigators as to whether it is primarily a MPD or MDS disease or both^{ref1, ref2}. The French-American-British group initially included CMML in its classification of MDS^ref. Later, there was an attempt to classify CMML into either the MPD category if the total WBC count was > 13,000 x 10⁹/L, or the MDS category if it was < 13,000 x 10⁹/L^ref . The FAB group recommended that patients who meet the criteria for the diagnosis of CMML be subdivided into CMML, MDS-like or CMML, MPD-like, depending on the degree of leukocytosis^ref. Clinical studies that divided patients according to the FAB suggestions, however, concluded that the magnitude of the WBC count does not identify subgroups that have major biologic or prognostic differences^{ref1, ref2}. To date, no specific cytogenetic or molecular differences between patients with predominantly MDS or MPD characteristics have been reported. Furthermore, some patients who initially manifest as having "nonproliferative" CMML, with low WBC counts and minimal if any splenomegaly, may eventually become quite "proliferative", with markedly elevated WBC counts^ref. For these reasons, the WHO committees chose not to divide CMML into these 2 subtypes. To emphasize the nosologic issues, CMML is placed in a separate category of diseases, the name of which clearly states the problem. The WHO classification does not make any significant changes in the criteria for the diagnosis of CMML. Despite the controversy over the disease category to which CMML belongs, there is one issue about which all investigators agree: the higher the blast count in CMML, the more unfavorable the prognosis^{ref1, ref2, ref3, ref4, ref5}. As a result, the WHO divides CMML into 2 prognostic categories, CMML-1 and CMML-2, based on the number of blasts in the blood and bone marrow.

Epidemiology : predominantly presents in the elderly^ref (Seymour JF, Cortes JE. Chronic myelomonocytic leukemia. In: Talpaz M, Kantajarian HM, eds. Medical Management of Chronic Myelogenous Leukemia. New York, NY: Marcel Dekker; 1998:43)
Pathogenesis : tyrosine kinase fusion genes :
• ETV6 (TEL)-PDGFRB t(5;12)(q33;p13), leading to constitutive activation of the tyrosine kinase domain of the PDGFR^ref. Multiple signaling pathways appear to be activated by TEL/PDGFßR^{ref1, ref2, ref3, ref4}
• HIP1-PDGFRB t(5;7)(q33;q11)
• H4-PDGFRB t(5;10)(q33;q21)
• RAB5-PDGFRB t(5;17)(q33;p13)
Most of the abnormalities are also routinely observed in patients with other MDS category diseases
• RAS gene mutations are observed in a significant proportion of patients (up to 40%) either at presentation or at some stage during the course of their disease^ref. The incidence of RAS mutations in CMML may be higher than in other MDS subtypes
Complete delineation of the relative contribution of these pathways to the pathogenesis of CMML will require further investigation, including the use of mouse models^{ref1, ref2}. TNF, GM-CSF, IL-3, IL-4, IL-6, and IL-10 have all been implicated as playing potential roles in the pathogenetic hyperproliferative growth pattern of CMML cells in vitro or in vivo in patients^{ref1, ref2, ref3, ref4, ref5, ref6}
Symptoms & signs : splenomegaly, monocytosis with granulocytosis, and thrombocytopenia.
Diagnostic criteria :
• persistent peripheral blood monocytosis > 1,000/ml
• no Philadelphia chromosome or BCR/ABL fusion gene
• < 20% blasts (include myeloblasts, monoblasts, and promonocytes) in the blood or bone marrow
• dysplasia in one or more myeloid lineages. If myelodysplasia is absent or minimal, the diagnosis of CMML may still be made if the other requirements are present and:
• an acquired, clonal cytogenetic abnormality is present in the marrow cells, or
• the monocytosis has been persistent for at least 3 months and all other causes of monocytosis have been excluded
• diagnose CMML-1 when blasts < 5% in peripheral blood and < 10% in bone marrow
• diagnose CMML-2 when one of the following occurs
• blasts 5-19% in peripheral blood
• blasts 10-19% in blood marrow
• Auer rods are present AND blasts < 20% in peripheral blood or bone marrow
• diagnose CMML-1 or CMML-2 with eosinophilia when the criteria above are present and when the eosinophil count in the peripheral blood is > 1,500/ml
Prognosis : sometimes it progresses to its acute counterpart (M4 AML)
Therapy :
• for the small subset of patients who demonstrate translocations in their leukemia cells involving PDGFßR, imatinib mesylate (STI571) has been recently reported to produce dramatic and durable responses^ref
• allogeneic HSCT :
• myeloablative HSCT : as most CMML patients are elderly at the time of diagnosis, it is not a viable option for the majority. For those patients who do have a donor and are young enough to tolerate the toxicities, myeloablative stem cell transplantation should be seriously considered, as this remains the only proven curative option for this disease
• nonmyeloablative allogeneic HSCT strategies are rapidly emerging and may ultimately prove to be a less toxic but effective alternative to myeloablative transplantation
• cytokine therapy and low- and high-dose chemotherapeutic options have been attempted, but with limited success. Part of the problem in interpreting many previous trials is that CMML patients have been treated, evaluated, and reported together with all other MDS subtypes, making specific evaluation of the response in CMML problematic
• EPO : responses can be observed in 15-20% of patients^ref.
• G-CSF or GM-CSF : CMML patients can also respond temporarily in terms of increases in peripheral blood neutrophil counts, but because CMML progenitor cells can also respond to these cytokines, there is a concern for a potentially higher transformation rate to AML^ref
• given the toxicities of high-dose chemotherapy in this elderly patient population, chemotherapeutic trials have generally not produced sufficient response rates to justify routine use of high-dose chemotherapy
• farnesyltransferase inhibitors (FTIs) were developed as specific compounds to block Ras signal transduction by inhibiting Ras binding to the inner plasma membrane^ref. Whether this is their true or primary mechanism of action is a matter of ongoing debate, but mounting evidence suggests that response of malignancies to FTIs is independent of RAS mutational status^{ref1, ref2, ref3}. Investigators from Stanford have recently reported preliminary results of the use of one FTI, R115777, in a Phase I/II study of MPD patients, including 2 CMML patients (Gotlib J, Dugan K, Katamneni U, et al. Phase I/II study of farnesyltransferase inhibitor R115777 (Zarnestra) in patients with myeloproliferative disorders (MPDs): preliminary results [abstract]. ASCO Proceed. 2002;21:4a). Further results from this and similar trials will be of interest
• blocking GM-CSF at the cell surface, is also a potentially viable approach to targeted therapy. 2 compounds discussed below, E21R and DT388-GM-CSF, are entering trials in adults and children for various myeloid malignancies and may prove efficacious in CMML
• atypical chronic myeloid leukemia (aCML) is not an ideal name for any disease, because it implies that the associated disorder is merely an atypical variant of chronic myelogenous leukemia (CML). Instead, aCML lacks the Philadelphia (Ph) chromosome and BCR/ABL fusion gene that are the hallmarks of classic CML. In addition, aCML is associated with marked granulocytic and often multilineage dysplasia, which is not observed during the chronic phase of CML. Although the WHO committees struggled for a better name for aCML to avoid the possibility of confusion with CML, none could be agreed upon. However, the placement of aCML in a different disease category does serve to set it apart from CML

Epidemiology : atypical CML affects a truly heterogeneous group of patients (mostly aged 60-70), and the exact incidence is not known (1-2 cases every 100 typical CML). Reports of small numbers of these patients indicate that they often have other cytogenetic abnormalities and suffer from short median survival times. Because of the paucity of these patients and their vast clinical heterogeneity, little can be said regarding pathogenesis
Pathogenesis :
• t(5;10)(q33;q21) : fusion of H4/D10S170 to PDGFRß^ref
Laboratory examinations :
• WBC = 35,000-300,000/ml
• blasts 5-20% in peripheral blood, < 20% in bone marrow
• promeylocytes, myelocytes, metamyelocytes = 10-20%
• monocytes < 10%
• LAP normal, reduced or increased
• cytogenetics : +8, +13, del(20q), i(17q), del(12p)
Prognosis : the few clinical studies published to date indicate that aCML is clinically a very aggressive disease, with reported median survival times of only 11 to 18 months^{ref1, ref2}
Therapy : preliminary findings indicate that these patients generally do not respond to imatinib mesylate. Other potential treatment options to consider are a clinical trial, if available, allogeneic HSCT, or low-dose chemotherapy such as hydroxyurea
• juvenile myelomonocytic leukemia (JMML) is a clonal hematopoietic disorder characterized by proliferation principally of the neutrophil and monocytic lineages. It lacks the Ph chromosome and BCR/ABL fusion gene and manifests as a leukemic disorder in infants and young children, although adolescents may occasionally be affected as well. The criteria utilized in the WHO classification for JMML follow the guidelines established by the European Working Group of MDS in Childhood^ref. This entity incorporates those leukemias of childhood previously referred to as juvenile chronic myeloid leukemia and chronic myelomonocytic leukemia^ref. Cases previously referred to as the infantile monosomy 7 syndrome are also included in this category^ref.

Epidemiology : afflicts infants and young children, with the vast majority of cases presenting when children are <= 5 years of age
Aetiology : neurofibromatosis type 1
Pathogenesis : much more is known about the pathogenesis of JMML than about that of CMML and aCML. JMML is a clonal disorder arising from the pluripotent stem cell^{ref1, ref2}. More so than any other leukemia or myeloproliferative disorder, JMML cells in vitro nearly uniformly show spontaneous colony formation without addition of exogenous growth factors. Constitutive signaling of the Ras pathway^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8} (75%) : these subsets remain mutually exclusive^{ref1, ref2, ref3}
• activating RAS point mutations (20%)
• inactivating NF1 mutations (30%) : murine hematopoietic cells that are homozygously deleted of Nf1 (Nf1^-/-) are also hypersensitive to GM-CSF and, if these cells are transplanted into irradiated recipient mice, they are capable of inducing an MPD reminiscent of JMML^{ref1, ref2}. Nf1 mutant murine hematopoietic cells demonstrate hyperactivation to numerous cytokines, including GM-CSF, SCF, and IL-3^ref. However, studies by Birnbaum and colleagues with Gmcsf-Nf1 doubly mutant cells have shown that GM-CSF plays a central role in the aberrant growth of Nf1 mutant cells^ref, thus providing a compelling rationale for pursuing therapeutic strategies that target the GM-CSF signal transduction pathway in JMML patients.
• mutations in PTPN11 (25%)
... results in JMML cells demonstrating a selective hypersensitivity to GM-CSF^ref.
Symptoms & signs : marked hepatosplenomegaly, fever, fatigue, infections, hemorrhages, maculopapular rash (40-50%), evolution to T-cell lymphoma^ref
Laboratory examinations :
• leukocytosis (25,000-100,000/ml) with monocytosis (> 1,000/ml; 5-30%), anemia and thrombocytopenia
• elevated fetal hemoglobin in most patients (even when corrected for age)^ref
• cytogenetics : most patients (> 80%) have a normal karyotype and are, by definition, Philadelphia chromosome negative and BCR/ABL^-; monosomy 7 (30-40%), RAS (20%), NF1
Therapy : there is no known, consistently effective therapy for JMML. Single- and multiagent chemotherapy regimens in limited numbers of patients report widely varying response rates but provide little evidence that such therapy improves ultimate outcome
• only allogeneic HSCT has resulted in extended survival^{ref1, ref2, ref3}. Unfortunately, the relapse rate from allogeneic SCT is inordinately high in JMML, ranging from 28-55% in several studies, with 5-year disease-free survival rates ranging from only 25-40%. Although 13-cis retinoic acid can produce a 40-50% overall response rate, complete remissions sustained off therapy are rare
• given the knowledge of JMML pathogenesis, mechanism-based molecularly targeted approaches such as that used for imatinib mesylate in BCR/ABL⁺ CML now seem justifiable for JMML. However, given that SCT can result in long-term survival, it seemed inappropriate to completely abandon this treatment approach. Therefore, a Phase II window/Phase III trial design for JMML was activated by the Children’s Oncology Group in 2001.
• farnesyltransferase inhibitor (FTI) R115777 x 2 months =>
• begin 13-cis retinoic acid (100 mg/m²), 2 courses of fludarabine + ara-C for tumor de-bulking =>
• splenectomy + 13-cis RA =>
• allogeneic HSCT =>
• 13-cis RA for 1 year to prevent relapse
There are 3 appealing aspects to this protocol design. First, it permits the rigorous evaluation of the efficacy of a single molecularly targeted agent in untreated JMML patients who have not yet developed drug resistance. Second, if one phase II agent fails, the protocol is designed to allow for the substitution of a different agent for Phase II testing without disrupting the rest of the study. Finally, the fact that participation in the Phase II window is not required allows patients and their parents who are skeptical regarding experimental agents an opportunity to still enroll in the remainder of the protocol. The first agent to be tested in this format for JMML is the FTI R115777, the same agent being tested in adults with MPD (Gotlib J, Dugan K, Katamneni U, et al. Phase I/II study of farnesyltransferase inhibitor R115777 (Zarnestra) in patients with myeloproliferative disorders (MPDs): preliminary results [abstract]. ASCO Proceed. 2002;21:4a). A multitude of other agents capable of targeting the GM-CSF/Ras pathway (albeit with varying degrees of specificity) are now emerging as potential capable agents that can substitute into the Phase II window of this protocol once R115777 has completed testing.
• peptidomimetics : E21R was created by a single amino acid substitution in the GM-CSF molecule at position 21. This substitution allows E21R to function as a GM-CSF antagonist by binding to the -subunit of the GM-CSF receptor but preventing its association with the ß-subunit, which is critical for downstream signal transduction. At concentrations of 1 µg/mL and 10 µg/mL, E21R induced apoptosis in AML and CML cells^ref, and in JMML cells^ref, respectively. In a JMML-SCID/NOD mouse model^ref, E21R prevented dissemination of leukemic cells and induced remission in animals that had developed JMML-like MPD after injection of human JMML cells. E21R is in Phase II studies in adult AML and CMML in England and Australia. A Phase I trial in relapsed pediatric myeloid malignancies is in the planning stages in the USA
• GM-CSF fused to toxins : 2 groups have reported the successful development of a GM-CSF molecule/diphtheria toxin fusion construct^{ref1, ref2}. This fusion product has shown some effectiveness in toxicity to acute leukemia cells and JMML cells^ref. A Phase I trial of this agent has been conducted in relapsed adult AML.
• other signaling inhibitors : a DNA enzyme that targets Raf-1 gene expression has shown effectiveness at JMML cell growth inhibition in vitro and in a JMML NOD-SCID mouse model^ref. The Nf1 JMML mouse model provides a useful system for testing targeted therapeutics such as the MEK inhibitor PD184352^ref. These ongoing studies demonstrate the utility of both the Nf1 and NOD/SCID JMML mouse models to not only help elucidate pathogenetic mechanisms but also to test molecularly targeted therapeutics.
• since donor lymphocyte infusions have clinical activity in JMML, T cell mediated immunotherapy could provide a nonredundant treatment approach to compliment current therapies. g-globin, an oncofetal protein overexpressed by clonogenic JMML cells, may serve as a target of an anti-tumor immune response. 5 g-globin derived peptides were predicted as potential HLA-A2 restricted CTL epitopes and 4 (g031, g071, g105, and g106) were shown to bind A2 molecules in vitro. Using an artificial antigen presenting cell (aAPC) that can process both the N- and C-termini of endogenously expressed proteins, we biochemically confirmed that g105 is naturally processed and presented by cell surface A2. Furthermore, g105 specific CD8⁺ CTL generated from A2 positive healthy donors were able to specifically cytolyze g-globin⁺, but not g-globin^-, JMML cells in an A2 restricted manner. These results suggest that this aAPC-based approach enables the biochemical identification of CD8⁺ T cell epitopes that are processed and presented by intact cells and that CTL immunotherapy of JMML could be directed against the g-globin derived epitope g105^ref.
Prognosis : 1-yr OS = 70% (higher in patients < 1 year). Negative prognostic factor : PLT < 30,000/ml and HbF > 15%. 10-20% progress to AML
• chronic eosinophilic leukemia (CEL) (and the hypereosinophilic syndrome (HES))


• myelodysplastic/myeloproliferative disease, unclassifiable (MDS/MPD-U)
• refractory anemia with ringed sideroblast and thrombocytosis (RARS-T) : however, the use of the term RARS-T should be restricted to patients who display both dyserythropoiesis (in addition to ringed sideroblasts) and megakaryocytes similar to those in ET, PV or PMF^{ref1, ref2}

Aetiology : JAK2 V617F mutation^ref

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