Mixed phenotype acute leukemia with t(9;22): success with nonacute myeloid leukemia-type intensive induction therapy and stem cell transplantation.

Mixed phenotype acute leukemia with t(9;22) is a rare disease with poor prognosis, and information on optimal treatment is limited. We describe a case where our patient experienced positive outcome after nonacute myeloid leukemia-type intensive induction therapy followed by postremission therapy with stem cell transplant.

Introduction

The Philadelphia chromosome (Ph+) is derived from t(9;22)(q34; q11) or variants and carries the chimeric BCR/ABL1 fusion gene which is classically associated with chronic myeloid leukemia (CML) 1. Chimeric BCR/ABL1 fusion transcript e13a2(b2a2)/e14a2(b3a2) encodes for a 210‐kDa protein (P210), e1a2 encodes for a 190‐kDa protein (P190), and less commonly e19a2 encodes for a 230‐kDa protein (P230) resulting in constitutively active tyrosine kinase that leads to oncogenic transformation of cell to leukemia 2.

Ph+ is found in 15–30% of adults and 2–5% of children with acute lymphoblastic leukemia (ALL), and on rare occasions, <3%, in acute myeloid leukemia (AML) 3. Ph+ lymphoma and myeloma have been described in the literature 4, 5.

Among mixed phenotype leukemia with abnormal cytogenetics, up to 20% are reported Ph+ 6. Acute leukemia presenting with Ph+ blasts can mean CML in myeloid blast crisis (CML/MBC), Ph+ ALL, Ph+ AML, or Ph+ mixed phenotype acute leukemia. Certain features such as the presence of basophilia, often seen in CML/MBC, or the absence of basophilia commonly seen in Ph+ AML can help distinguish one from the other 7. However, it can be very challenging to delineate these separate entities even in expert hands. Efforts are being made to characterize the genetic differences between the malignancies to better manage treatment as these patients typically have poor prognosis 3.

Mixed phenotype acute leukemia patients with t(9;22) or 11q23 cytogenetic abnormalities have very adverse prognosis 8. Central nerves system (CNS) involving leukemia add to the disease complexity as extramedullary AML with marrow involvement is considered independent adverse prognostic factor with 5‐year survival rate ranging from 20% to 30% 9.

Here, we present a challenging case of Ph+ AML with CNS involvement treated with intensive chemotherapy, tyrosine kinase inhibitor (TKI), CNS directed therapy, and achieved lasting remission after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Patient is in complete remission for over 18 months despite its poor prognosis and remains on maintenance TKI for relapse prevention.

Case Presentation

A previously healthy 61‐year‐old man presented with easy bruising, slow wound healing sustained during routine household chores, and general malaise for the past 3 months. Physical examination revealed petechiae on lower extremity, mild splenomegaly, and axillary adenopathy. Ultrasound of the abdomen confirmed enlarged spleen measuring 13.3 cm. Initial laboratory workup was concerning for leukemia (Table 1). Complete blood count (CBC) showed significant leukocytosis with white blood count of 150,100/μL, normocytic anemia with hemoglobin of 6.7 g/dL, and thrombocytopenia with platelet count of 37,000/μL. The differential was notable for 84.6% blasts and absence of basophilia. Lactate dehydrogenase (LDH) was markedly elevated at 785 IU/L.

Table 1

Initial laboratory workup

Name	Value	Reference	Unit
White cell count	150.1	3.4–10.4	1000/μL
Red blood cell count	2.26	4.4–5.6	10e6/μL
Hemoglobin	6.7	13.5–17.5	g/dL
Hematocrit	20.6	40.0–48.0	%
MCV	91.2	80–100	fL
MCH	29.6	27.0–34.0	pg
MCHC	32.4	32.0–35.0	%
RBC distribution width	17.1	<14.6
Mean platelet volume	6.7	5.5–9.0	fL
Platelet count	37	150–425	1000/μL
Neutrophils	0.8		%
Lymphocytes	7.7		%
Eosinophils	0		%
Monocytes	5.1		%
Basophils	0		%
Myelocytes	0.9		%
Blasts	84.6		%
Myelocytes (Absolute)	1.35	0	1000/μL
Neutrophils (Absolute)	1.20	1.8–7.8	1000/μL
Lymphocytes (Absolute)	11.56	1.0–4.8	1000/μL
Eosinophils (Absolute)	0.0	0.0–0.3	1000/μL
Basophils (Absolute)	0.0	0.0–0.1	1000/μL
Blasts	126.98	0	1000/μL
LDH	785	125–243	IU/L

Bone marrow biopsy (BMB) showed diffuse infiltration by numerous blast cells, which effaced the normal marrow architecture (Fig. 1A). A large number of blast cells were also evident on the aspirate (Fig. 1B). Cytogenetics and fluorescence in situ hybridization (FISH) analysis revealed the loss of chromosome 7 and the presence of Philadelphia chromosome: 45,XY,‐7, t(9;22)(q34;q11.2)[19]/46,XY[1]. Blasts had minimally differentiated phenotype. Morphologically these cells were atypical with immature expression of CD34 and co‐expression of CD13 and HLA‐DR favoring an early myeloid differentiation rather than lymphoid origin. Flow cytometry on the marrow aspirate showed an abnormal population of cells expressing dim CD45, moderate CD19, dim CD13, bright CD34, HLA‐DR, with a subset expressing dim CD117, dim MPO, and dim TdT is identified, comprising 72% of total events. An atypical subset of CD14 + CD64 + monocytes expresses dim CD2. These blasts were negative for surface kappa and surface lambda light chain immunoglobulins, as well as CD10, CD11b, CD14, CD16, CD64, CD56. Molecular studies showed BCR/ABL p190 mRNA PCR of 33.8% on international scale and negative p210. NPM1, FLT3, KIT, and CEPBA mutations were not detected.

Figure 1

(A) Core biopsy of the marrow showed diffuse infiltration by numerous blast cells, which effaced the normal marrow architecture (H&E, x400). (B) A large number of blast cells are also evident in the marrow aspirate (Wirght Giemsa, x1000).

On admission, patient was started on hydroxyurea for cytoreduction along with routine tumor lysis prophylaxis with hydration and allopurinol. Dasatinib was started after 2 days once initial reports became available showing positive Philadelphia chromosome. Patient was then started on hyper‐CVAD a few days later after extensive discussions about therapy choice. Five days after admission, patient developed headache, blurry vision, and floaters bilaterally. A computerized tomography (CT) of head was performed, and it did not show any acute intracranial bleed, mass, or midline shift. Blood pressure was normotensive. Ophthalmology was consulted, and they noted the following on fundus examination: Right eye has preretinal hemorrhage near fovea and left eye with intraretinal and preretinal hemorrhage. Their final impression was preretinal hemorrhages on both eyes and intraretinal hemorrhages on left eye secondary to thrombocytopenia. He underwent lumbar puncture (LP), and eight blasts were found in cerebral spinal fluid (CSF) on smear consistent with CNS involvement with leukemia.

Patient was placed on hyper‐CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) with dasatinib 100 mg daily. Biweekly intrathecal chemotherapy including intrathecal cytarabine (AraC) was initiated with subsequent LP showing clearance of blast cells in CSF. His blurry vision also resolved. Patient completed the 2‐course hyper‐CVAD regimen with good response. Dasatinib was continued throughout his treatment course, and no significant adverse effect was noted. Kinase domain mutation was not checked. BMB performed 3 months after diagnosis showed mildly hypocellular bone marrow without morphologic or immunophenotypic evidence of AML. Patient achieved complete cytogenetic response (CCyR) and major molecular response (MMR) at this point. Due to the high risk of relapse in Ph+ AML, patient subsequently received allo‐HSCT. He had 10/10 HLA‐matched haploidentical allo‐HSCT from his brother (a total of 4.31 × 10e6 CD34+ cells were transfused) with conditioning regimen consists of cyclophosphamide 60 mg/kg and total body irradiation (TBI) 1200 centigray (cGy). His course was complicated by chronic graft‐versus‐host disease (GVHD), but overall patient had been doing well for more than 18 months. Patient continued on dasatinib with plan to stop after 2 years from the date of allo‐HSCT. Dose reduction and interruption were performed to improve tolerance due to gastrointestinal‐related side effects. His BMB showed 100% donor chimerism and negative cytogenetics. FISH study for t(9;22) was negative, and monthly BCR/ABL p190 mRNA PCR level remained negative. By all tests, patient is in complete remission and minimal residual disease (MRD) negative.

Discussion

Philadelphia chromosome‐positive de novo AML is a rare condition with estimated incidence rate of 0.5–3% 1, 6, 10. The 2016 revision of the World Health Organization (WHO) classification has recognized mixed phenotype AML with t(9;22) as a separate entity 11. Distinction between unrecognized CML/MBC and de novo AML is possible on many grounds. Compare to CML/MBC, patients with Ph+ AML lack a history of CML or chronic phase/accelerated phase CML after AML induction chemotherapy. Coexistence of normal metaphases along with Ph+ metaphases, absence of basophilia, and lack of moderate/massive splenomegaly at the time of diagnosis favors Ph+ AML over CML/MBC 3, 12. Normal karyotype after induction therapy is suggestive of Ph+ acute leukemia, and in CML/MBC, cytogenetic abnormality often persist 13. In addition to the t(9;22), CML/MBC is associated with trisomy 8, trisomy 19, and isochromosome 17q, whereas monosomy (‐7) is associated with Ph+ AML 1, 3, 14. The p190 BCR‐ABL fusion protein is common in Ph+ AML but only rarely present in CML/MBC 1. On the molecular level, Konoplev et al. found 22% of its patients with Ph+ AML had NPM1 mutation and none in patients with CML/MBC 2. Ph+ AML also has a higher prevalence of FLT3 and KIT genes 2. While none of the aforementioned features alone is diagnostic of Ph+ AML, the summation provides a good indicator of the correct diagnosis, which is important because of its potential treatment implications.

Outcome of Ph+ AML is generally poor with some studies showed median survival of 9–18 months 1, 14. The mainstay of treatment includes imatinib and allo‐HSCT, but the optimal treatment is not clear because of the limited number of cases and short follow‐up reported in literature. With the presence of Ph chromosome, complete response is thought to be unlikely with imatinib alone 1. Therefore, allo‐HSCT is frequently initiated if patient is a transplant candidate. Current recommendation according to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for AML is to treat Ph+ AML as CML/MBC with TKI (alone or with induction chemotherapy) followed by allo‐HSCT 15. A recent study by Chantepie et al. showed a promising 68% 2‐year overall survival in patients with Ph+ AML after receiving allo‐HSCT 10. There are also reports that showed benefits with using imatinib as interim therapy prior to allo‐HSCT and even imatinib or later generations of TKI alone 16, 17, 18. Reboursiere et al. reported 21 cases of patients with Ph+ AML in the literature treated with TKI therapy 1. Eight of the patients received allo‐HSCT and three of them continued TKI as maintenance therapy afterward. These patients did well with at least >18 months survival. It appears TKI after allo‐HSCT provides survival benefits, but it is far from conclusive at this point given the limited number of cases reported. More studies will be needed to elucidate the best treatment in this rare subtype of AML.

Any type of AML with CNS involvement is uncommon with incidence rate range from 3.1% to 3.6% 19. Incidence rate is even lower at 0.37% when CNS involvement is found at diagnosis according to a study conducted by Shihadeh et al. 20. These patients tend to be younger, have a higher white blood cell (WBC) count, lactate dehydrogenase (LDH), and peripheral blood blasts at diagnosis 19, 20. One study found 80% of patients with CNS involvement had LDH levels >700 IU/L 19. Other predictive factors include FLT3‐ITD, African American ethnicity, and cytogenetic abnormalities of chromosome 11, inv(16), and trisomy(8) 20. Unlike acute ALL where CNS involvement is more common in which routine intrathecal prophylaxis chemotherapy at the time of diagnosis has shown benefits, such prophylactic measure is not recommended for AML due to the lack of supporting data. Different treatment options include intrathecal chemotherapy, systemic chemotherapy, and brain/craniospinal radiation 20. It is important to note that AML with CNS involvement confers a worse disease‐free and overall survival (OS) compared to those without CNS involvement, so any clinical suspicion should prompt timely diagnostic workup such as lumbar puncture and/or head imaging 19.

Our patient presented with features that are suggestive of primary Ph+ AML including no history of chronic phase, a lack of basophilia, monosomy (‐7), and positive p190. His course was complicated by CNS involvement at diagnosis, and he had a number of predictive factors such as high WBC, LDH, blasts, and chromosome 11 abnormalities. Patients with biphenotypic acute leukemia treated with ALL‐based induction regimen have reported 87% complete remission (CR) while only 20% of patients treated with an AML‐based regimen achieved CR 21. Based on strongly favorable data of intrathecal component to treat CNS disease, we started our patient on the hyper‐CVAD regimen with dasatinib 21. He was successfully treated and later received allo‐HSCT who is now in complete remission for more than 18 months.

Conclusion

Philadelphia chromosome‐positive mixed phenotype de novo AML is rare and can be challenging to distinguish from CML/MBC. Features associated with Ph+ AML include lack of chronic phase, absence of basophilia or splenomegaly, monosomy (‐7), NPM1 mutation, and presence of p190. CNS involvement in mixed lineage leukemia is an adverse prognostic factor. Any clinical suspicion of neurologic involvement requires timely workup to improve outcome. Non‐AML‐type intensive induction therapy followed by postremission therapy by allo‐HSCT in suitable patients can potentially overcome adverse prognostic factors, achieve complete remission with long‐term survival, and be cured.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this article.

Authorship

OC: reviewed the literature and wrote the article. FA: treated the patient and collected the patient data. FA, AJ, and RK: corrected the manuscript and made helpful suggestions. RM: performed the histological analyses and various stainings. All authors read and approved the final manuscript.