Philadelphia chromosome‐negative acute leukemia in patients with chronic myeloid leukemia
Authors: Zimu Gong, Mina L. Xu, Mingyi Chen, Wei Cui, Hagop M. Kantarjian, Jorge E. Cortes, Ting Zhou, Guilin Tang, Wei Wang, L. Jeffrey Medeiros, Shimin Hu
Journal: American Journal of Hematology (2019)

To the Editor: Chronic myeloid leukemia (CML) is characterized by the presence of BCR-ABL1, usually in the form of the Philadelphia chromosome (Ph) as a result of t(9;22)(q34;q11.2). Blast phase (BP), the terminal stage of CML, often has clinical and laboratory manifestations that mimic those of de novo acute leukemia. The presence of increased blasts and suppression of normal hematopoiesis almost always indicate disease progression of CML. Rarely, CML patients may develop dysplasia and increased blasts without the Ph, indicating a secondary Ph-negative (Ph−) hematologic malignancy, either a myelodysplastic syndrome (MDS) or Ph-negative acute leukemia. In most of these patients, the Ph− secondary hematologic malignancy presents initially as MDS, which may later progress to acute myeloid leukemia (AML). The Ph− acute leukemia without an antecedent MDS is extremely rare, and it is often challenging to distinguish this disease entity from sudden onset CML BP. Cytogenetic analysis is indispensable in the diagnosis and monitoring of CML. Additional chromosomal abnormalities (ACAs) in Ph+ clones of CML are observed in about 5% of patients diagnosed with chronic phase disease. Generally, ACAs are associated with disease progression and inferior outcome, and are currently a part of staging criteria of CML. In contrast, the clinical significance of clonal cytogenetic abnormalities (CCAs) in Ph− clones is less understood. Issa et al. found that CCAs other than -Y in Ph− clones increased the risk of blastic progression of CML, and negatively affected patient survival.1 However, the association between CCAs in Ph− clones and development of a Ph− secondary hematologic malignancy remains unclear. In this retrospective study, we investigated the frequency and characteristics of Ph− acute leukemia without an antecedent MDS in adult CML patients. Patients with cryptic Ph were excluded. A total of 2985 CML patients who were diagnosed and/or followed up at MD Anderson Cancer Center were reviewed, and five patients with Ph− acute leukemia, without an antecedent MDS were identified. Two patients were reported previously.2, 3 Three additional cases were contributed from outside institutions, forming a study cohort of eight patients. There were three men and five women, with a median age of 53 years (range, 40-78 years) at time of diagnosis of CML (Table 1). At initial diagnosis of CML, seven patients were in chronic phase, and one in myeloid BP (patient #8). Six patients had P210 (e13a2 and/or e14a2) BCR-ABL1 transcripts, and one patient (#8) had P190 (e1a2) transcripts; the transcript subtype was unknown in one patient. Two patients had ACAs at initial diagnosis: -Y in patient #2 and complex karyotype in patient #8. No patient had CCAs in Ph− clones at initial diagnosis of CML. All patients received tyrosine kinase inhibitors (TKIs). Additionally, patient #8 received conventional 3 + 7 chemotherapy. CML: 46,XY,t(9;22)(q34;q11.2) [20] Ph- AL: 46,XY,t(11;17)(q23;q25) [20] MLL+ by FISH CML: 45,X,-Y,t(9;22)(q34;q11) [20] Ph- AL: 45,XY,-7[18]/45,X,-Y,t(9;22)(q34;q11.2) [2] CML: 46,XY,t(9;22)(q34;q11.2) [20] Ph- AL: 45,XY,-7[20] CML: 46,XX,t(9;22) (q34;q11.2) [8] Ph- AL: 46,XY [20] CML: 46,XX,t(9;22)(q34;q11) [20] Ph- AL: 46,XX [20] CML: t(9;22) Ph- AL: 47,XX,+8[20] CML: 46,XX,der(9)del(9)(q34)t(9;22)(q34;q11.2),der(22)t(9;22) [20] Ph- AL: 46,XX [15] CML: 46,XX,add(3)(q21),del(5)(q22q35),add(6)(q25), t(9;22)(q34,q11.2),add(19)(p13)[cp19] Ph- AL: 45,XX,der(3)(q12q21)del(3)(q21q25),del(5)(q13q33), add(6)(q25), 7,add(7)(p21) [13]/45,idem,i(11)(q10) [5]/ 45,idem,t(5;15)(p10;q10) [2] After a median follow-up time of 42.4 months (range, 5.7-187.2 months) from initial diagnosis of CML, all eight patients developed Ph− acute myeloid leukemia (AML), six of which were initially misdiagnosed as myeloid BP of CML. At diagnosis of Ph− AML, three patients had monosomy 7 (−7) in Ph− clones including one with a complex karyotype, three patients had a normal diploid karyotype, one patient had trisomy 8, and one patient had t(11;17)(q23;q25) with KMT2A rearrangement, confirmed by fluorescence in situ hybridization analysis. Seven patients had bone marrow aspiration and biopsy specimens available for morphologic review, and six had a variable degree of dysplastic changes at the time of diagnosis of Ph− AML. Various molecular mutation panels were performed in six patients at time of diagnosis of Ph− AML: FLT3 ITD was observed in patients #3 and #4; mutations of KRAS, RUNX1, PHF6, and WT1 in patient #4; NPM1 mutation in patient #5; and SRSF2 mutation in patient #6. Of the six patients with available treatment information, three received combined chemotherapy (patients #1, #2, and #4), two received hypomethylating agents (patients #5 and #6), and one received hydroxyurea (patient #3). At last follow-up, four patients died with refractory or progressive Ph− AML at 2, 4, 5, and 10 months after diagnosis of Ph− AML, respectively. Also, two patients were alive with refractory disease after 0.8 and 11 months, one patient (#4) underwent allogeneic stem cell transplant and remained disease-free at 65.5 months, and one patient was lost in follow-up. A comprehensive literature review revealed 14 cases of Ph− acute leukemia in CML patients, without an antecedent MDS (Supplementary Table 1). Combining our cohort of eight cases of Ph- AML with those in the literature, there were 14 men and eight women with a median age of 52 years (range, 22-81 years). Twenty developed AML and two developed B-lymphoblastic leukemia. The median time interval from initial diagnosis of CML to the diagnosis of Ph− acute leukemia was 46.9 months (range, 5.7-187 months). The median survival was eight months after the development of Ph− acute leukemia, similar to that of patients with myeloid BP of CML. Common CCAs in Ph− clones in these patients included: −7/7q- [n = 9, including 1 with add(7)(q22)]; reciprocal rearrangements [n = 6, including 2 t(15;17), 1 inv(3), 1 t(8;21), 1 t(11;17)/MLL, and others]; complex karyotype (n = 4); and + 8 (n = 2, including one with a complex karyotype). The CCAs in Ph− clones in Ph− acute leukemia follow a nonrandom pattern. It is known that −7 is a rare CCA in Ph− clones, with a reported frequency of 6.9%, but it is enriched in Ph− acute leukemia. In contrast, +8 is the most common ACA in Ph+ clones and the most common CCA in Ph− clones, but is rare in Ph− acute leukemia. These data support a role for −7 in the development of Ph− acute leukemia. Interestingly, −7 is associated with a high risk, and + 8 is associated with a low risk of progression to CML-BP when present in Ph+ clones. Whereas a lymphoblastic phenotype is observed in over 30% of CML-BP cases, it is much less common in Ph− acute leukemia (<10%). It remains to be seen what mechanisms drive the higher likelihood of CML patients to develop Ph− AML, instead of Ph− lymphoblastic leukemia. Several potential mechanisms may explain the development of CCAs in Ph− clones and Ph− acute leukemia in CML patients. First, the emergence of Ph may not be the initial event in CML development, and clonal hematopoiesis may have started before the Ph is observed. With TKI therapy, the Ph+ clones are suppressed and Ph− clones emerge. Quintás-Cardama et al. reported a case of Ph− extramedullary myeloid disease in a CML patient. The bone marrow karyotype at initial diagnosis of CML was: 46,XY,der(7)t(7;11)(p12;p11.2)add(7)(q35),der(11)add(11)(p11.2) [14]/46,XY,der(7)t(7;11)(p12;p11.2)add(7)(q35),t(9;22)(q34;q11.2),add(11)(p11.2) [3]/46,XY [3]. The karyotype was 46,XY,der(7)t(7;11)(p12;p11.2)add(7)q(35),add(11)(p11.2)[17]/46,XY[3] when the patient developed Ph− extramedullary myeloid disease.4 The presence of chromosome 7 and 11 abnormalities in both Ph+ and Ph− clones is suggestive of clonal hematopoiesis before the emergence of Ph. Conversely, it is possible that the development of Ph− acute leukemia may be clonally unrelated to CML. Genomic analysis performed on two patients who developed Ph− AML in the setting of CML revealed that the AML and CML arose independently in both patients.5 Lastly, imatinib suppresses the activity of cellular ABL in normal cells. ABL is a crucial player in DNA damage repair pathways. Inhibition of ABL results in increased susceptibility to DNA damage and cytogenetic instability, and contributes to the development of secondary hematologic malignancy. This is supported by the development of MDS with −7 in a case of gastrointestinal stromal tumor following imatinib treatment.6 Given the high frequency of −7 and morphologic dysplasia in Ph− acute leukemia, it is possible that an antecedent stage of MDS before development of Ph− acute leukemia was not detected in these patients. Chemotherapy remains a cornerstone in the management of both CML-BP and Ph− acute leukemia. In selected patients, stem cell transplantation may provide durable remission, as observed in patient #2 in our cohort, as well as in four transplant recipients identified in our literature review. Additionally, patients who develop acute promyelocytic leukemia with PML-RARA fusion will likely benefit from all-trans retinoic acid treatment.7, 8 While TKIs provide survival benefit to patients with CML-BP,9, 10 it is unclear whether TKIs should be continued in CML patients once Ph− acute leukemia occurs. In most Ph− acute leukemia patients, the underlying CML is in remission, and it is potentially safe to hold TKI therapy while the patient receives treatment for acute leukemia to avoid the adversities of polypharmacy. For the subset of Ph− acute leukemia patients whose underlying CML is not in remission, it also may be acceptable to hold TKI therapy when the patient is receiving chemotherapy. That's considering the extremely aggressive course of Ph− acute leukemia, the relatively indolent behavior of the underlying CML, and the possible role of TKIs in development of Ph− acute leukemia. In summary, Ph− acute leukemia is a rare and dreadful complication in CML patients which poses a diagnostic challenge in the absence of cytogenetic analysis, particularly when it is not preceded by MDS. The prognosis of CML patients who develop Ph− acute leukemia is poor despite chemotherapy, and stem cell transplantation may be considered in carefully selected patients. 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