How I Treat In Brief
In “ How I Treat In Brief ,” we summarize recent “ How I Treat ” review articles , offering condensed versions of the diagnostic and therapeutic advice presented by experts in the field published in Blood . This month , Jason Gotlib , MD , discusses the diagnosis and treatment of patients with atypical chronic myeloid leukemia .
This material was repurposed from “ How I Treat Atypical Chronic Myeloid Leukemia ,” published in the February 16 , 2017 , edition of Blood .
TRAINING and EDUCATION
Atypical Chronic Myeloid Leukemia
typical chronic myeloid leukemia ( aCML ), BCR-ABL1 – negative is a rare myelodysplastic syndromes ( MDS )/ myeloproliferative neoplasm ( MPN ) for which no current standard of care exists .
Diagnosis of aCML
The diagnostic criteria that comprise the World Health Organization entity “ aCML , BCR-ABL1 negative ” represent a decades-long evolution of classifying diseases that exhibited morphologic similarity to CML but lacked both the Philadelphia ( Ph ) chromosome and BCR-ABL1 rearrangement .
Diagnosis of aCML first requires testing for the Ph chromosome and / or the BCR- ABL1 fusion gene to exclude classic CML .
In addition to histopathologic analysis of the peripheral blood ( PB ) and bone marrow ( BM ), contemporary evaluation of aCML should include myeloid mutation panel testing in addition to standard karyotyping .
Distinguishing aCML From Other Chronic Leukemias
Morphologic Criteria Some cases of aCML have been given the historical moniker “ CML-like syndrome ” because both diseases exhibit BMs with hyperplastic myeloid hyperplasia and PB leukocytosis characterized by a spectrum of myeloid immaturity . However , on morphologic grounds , this is where the similarity ends .
Unlike BCR-ABL1 – positive CML , aCML is characterized by prominent dysplastic granulopoiesis ( e . g ., the acquired Pelger-Huët anomaly typical of MDS ; nuclear abnormalities including hypersegmentation , nuclear projections , and abnormally clumped nuclear chromatin ; and abnormalities of cytoplasmic granules ).
Multlineage dysplasia may be observed . In cases in which subtle dysplasia or borderline levels of myeloid immaturity or monocytosis are present , the morphologic distinction between aCML , BCR-ABL1 – positive CML , chronic myelomonocytic leukemia ( CMML ), chronic neutrophilic leukemia , or MDS / MPN ( unclassified ) can be challenging .
The following criteria are associated with aCML , and can help distinguish aCML other chronic leukemias :
• ≥10 % immature myeloid cells ( promyelocytes , myelocytes , and metamyelocytes ) in the peripheral blood and / or dysplasia
• absent or minimally present basophilia (< 2 % of leukocytes )
• absent or minimally present monocytosis (< 10 % of leukocytes )
Genetic Features In contrast to CML , which is operationally defined by the presence of BCR-ABL1 , no single genetic lesion characterizes aCML . The mutations identified in aCML are commonly found in other myeloid neoplasms .
Some basic observations can be made about the molecular landscape of aCML : higher frequency mutations ( eg , > 20 %) include SETBP1 , ASXL1 , NRAS / KRAS , SRSF2 , and TET2 , and lower frequency mutations (< 10 %) include CBL , CSF3R , JAK2 , and ETNK1 .
Prognosis
Patients with aCML have an estimated median survival between 14 and 30 months . aCML tends to exhibit a more
FIGURE . Treatment Algorithm for aCML
Is pre-transplant disease cytoreduction required during HLA typing of potential donors ?
no
Proceed to alloHCT
Potentially actionable myeloid mutation ( s )
or
Consider therapy with targeted agent ( e . g . JAK inhibitor for JAK2 or CSF3R mutation ; or MEK inhibitor for RAS mutation ) on a clinical trial ( preferred ) or off-label basis yes
yes
Source : Gotlib J . How I treat atypical chronic myeloid leukemia . Blood . 2017 ; 129:838-45 .
Fast Facts
✓✓aCML is a rare MDS / MPN for which no current standard of care exists .
✓✓Next-generation sequencing may help to distinguish aCML from other chronic leukemias .
✓✓Common mutations identified in aCML include SETBP1 , ASXL1 , N / K-RAS , SRSF2 , and TET2 .
✓✓Treatment should include alloHCT for eligible patients . Other treatment strategies are co-opted from those used in MDS / MPN .
aggressive clinical course than other MDS / MPN subtypes .
Increased WBC count ( e . g ., cutoffs of > 40 × 10 9 / L or 50 × 10 9 / L ), increased percentage of peripheral blood immature precursors , female sex , and older age are adverse prognostic factors for overall survival or leukemia-free survival .
Treatment Options
No standard of care exists for the treatment of aCML , and no consensus recommendations or risk-based treatment algorithms exist to help guide a watchand-wait approach .
As seen in the FIGURE , my treatment algorithm begins with allogeneic hematopoietic cell transplantation ( alloHCT ) for
Diagnosis of aCML
HLA typing
Candidate for alloHCT ?
no
Myeloid mutation panel testing
HMAs ( decitabine or azacitidine ); secondline or adjunctive options include pegylated interferon alfa ; hydroxyurea , erythropoiesisstimulating agents
No currently actionable myeloid mutation ( s )
or
Clinical trial not based on an actionable mutation eligible patients , regardless of the results of mutation testing , and encompasses hypomethylating agents ( HMAs ) and targeted agents ( if mutation testing reveals a potentially actionable mutation ).
Treatment with HMAs in aCML is a rational application of their established activity in MDS and CMML , but the experience with HMAs in aCML is limited . I consider their use as a bridging therapy for transplant-eligible patients and as stand-alone treatment of patients without an alloHCT or clinical trial option .
Additionally , I co-opt treatment strategies used for either MDS or MPN and apply them on a case-by-case basis to address a patient ’ s major clinical manifestations ( e . g ., leukocytosis , anemia , constitutional symptoms , splenomegaly , and potential for progression to acute myeloid leukemia ). These secondline or adjunctive options may include JAK inhibitors ( in the rare instances when CSF3R T618I or JAK2 V617F is present ), pegylated interferon alfa , hydroxyurea , and / or erythropoiesis-stimulating agents .
Future Directions
Recent research has identified several promising therapeutic targets , including NRAS G12D , reactivation of the tumor suppressor PP2A , and SRSF2 mutations . Combination strategies using therapies targeting disease-associated mutations in conjunction with either HMAs or as an adjunct to alloHCT ( either as a bridge to transplant or in the posttransplant setting to reduce relapse ) should be evaluated .
Progress in aCML depends on enrollment of patients into clinical trials and molecular profiling of individuals , so that opportunities for targeted therapy can be exploited . ●
REFERENCE Gotlib J . How I treat atypical chronic myeloid leukemia . Blood . 2017 ; 129:838-45 .
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