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Year : 2016  |  Volume : 7  |  Issue : 2  |  Page : 66-69

A case series of patients with de novo Philadelphia-positive acute myeloid leukemia at a tertiary care center in South India - clinical profile, outcomes, and review of literature

Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

Date of Web Publication14-Jul-2016

Correspondence Address:
Suparna Ajit Rao
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Dr. M.H Marigowda Road, Bengaluru - 560 029, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1658-5127.186326

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Introduction: Ph+ AML is a well-recognized , but rare entity that poses challenges to clinicians to differentiate it from Chronic myeloid leukemia in blast crisis. Objective: Our aim was to study the clinical profile, treatment and outcomes of patients with Ph+ AML at our centre. Materials and Methods: Four cases of Ph+ AML entered in the hospital registry between 2013 and 2015 were identified and analysed. Results: The median age was 46 years with equal sex preponderance. The duration of presenting complaints was <3 months. Median presenting total count was 54,000 cells/cumm. 3 patients had mild splenomegaly. None had basophilia. There was no predominant FAB-subtype. The cytogenetics revealed abnormalities in addition to the Philadelphia chromosome in 2 patients.3 out of 4 patients received induction chemotherapy with 3+7 - cytosine arabinoside and daunomycin alon with Imatinib dosed at 400 mg/ day. They were all in hematological, morphological and cytogenetic remission following induction. None underwent allogenic stem cell transplant. Of the 4, one refused treatment and is lost to follow up. Of those who received induction chemotherapy, 2 received consolidation with high dose ARAC, of which- one completed consolidation (4 courses) and is in remission 27 months after diagnosis, and the other has completed 1st high dose consolidation (and is alive 3 months after diagnosis) and the third one received 3 courses of low dose subcutaneous ARAC due to poor tolerability and expired 7 months after diagnosis. Conclusions: Ph+ AML is rare with no clear treatment recommendations. Improved outcomes with tyrosine kinase inhibitors(TKI's) and stem cell transplant should prompt further studies. If patients remain in remission with long term TKI use, it could serve as an alternative to stem cell transplantation in low income countries.

Keywords: De novo Philadelphia-positive acute myeloid leukemia, rare, tyrosine kinase inhibitors

How to cite this article:
Loknatha D, Rao SA, Lokesh K N, Babu K G, Suresh Babu M C, Lakshmaiah K C. A case series of patients with de novo Philadelphia-positive acute myeloid leukemia at a tertiary care center in South India - clinical profile, outcomes, and review of literature. J Appl Hematol 2016;7:66-9

How to cite this URL:
Loknatha D, Rao SA, Lokesh K N, Babu K G, Suresh Babu M C, Lakshmaiah K C. A case series of patients with de novo Philadelphia-positive acute myeloid leukemia at a tertiary care center in South India - clinical profile, outcomes, and review of literature. J Appl Hematol [serial online] 2016 [cited 2023 Oct 3];7:66-9. Available from: https://www.jahjournal.org/text.asp?2016/7/2/66/186326

  Introduction Top

Philadelphia-positive (Ph+) acute myeloid leukemia (AML) is a very rare entity with little data available as to its incidence; optimal treatment regimen with the available data demonstrates very poor survival outcomes. The t(9;22)(q34;q11) results in the formation of a Ph chromosome and generates an active chimeric BCR-ABL tyrosine kinase. This chromosomal abnormality is most commonly associated with chronic myelogenous leukemia (CML) and precursor B-acute lymphoblastic leukemia. However, rare instances of patients with AML bearing this translocation (Ph+ AML) have been reported, constituting fewer than 1% of newly diagnosed cases of AML. [1] Controversy also exists as to whether it is a case of AML or CML in blast crisis, with few pointers used to distinguish both the entities. [1] We report here a series of cases of patients with Ph+ AML who received treatment and are on follow-up at our hospital.

  Materials and methods Top

Four patients of Ph+ AML were identified between 2013 and 2015. Ph+ AML cases were diagnosed in those who morphologically and immunophenotypically had AML with t(9 22). These cases presented with short duration history, with no/mild splenomegaly and no basophilia, making them more likely to be de novo AML cases. BCR-ABL transcripts were done using reverse transcription polymerase chain reaction at baseline; however, the breakpoint cluster region could not be done in our set up due to financial constraints. Responses were assessed according to the standard criteria.

  Results Top

The median age of our patients was 46 years (32-59) [Table 1], with equal sex preponderance. All had a short duration of presenting complaints of <3 months. The median total count at presentation was 54,000 cells/cumm (19,800 to >112,400/cumm), with a median of 43% blasts (30-81%) on the bone marrow aspiration. Three of the four patients had mild splenomegaly. None of our patients had basophilia or presented/developed extramedullary disease. There was no particular French-American-British (FAB)-subtype that was predominant. The cytogenetics revealed abnormalities in addition to the Ph chromosome in two of our four patients.
Table 1: Characteristics of our patients

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Three of the four patients received the standard induction chemotherapy and were initiated on oral imatinib dosed at 400 mg/day. They were all in hematological, morphological, and cytogenetic remission following induction. None of the patients were taken up for allogeneic stem cell transplant due to logistic issues. Of the four patients, one refused treatment and was lost to follow-up. Of the three who received induction chemotherapy, two received consolidation with high-dose Ara-C, of which one completed consolidation (four courses) and was in remission 27 months after diagnosis, one completed the first high-dose consolidation (alive 3 months after diagnosis), and one received three courses of low-dose subcutaneous Ara-C due to poor tolerability and expired 7 months after diagnosis.

  Discussion Top

Ph+ AML is a very rare entity and the limited literature available worldwide shows dismal outcomes with a median survival of 6 to 9 months, [1],[2],[3],[4] especially in the patients who did not receive allogenic stem cell transplant. We detected only 4 such cases from 2013 to 2015 at our centre. The characteristics of our patients in comparison with other studies is summarized in [Table 2]. [1],[2],[3],[4],[5],[6],[7] Its incidence is < 1% of all AML in various series. [1],[2],[3],[6],[8],[9],[10]
Table 2: Comparison with other studies - with respect to clinical profile, outcomes

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The median age of these patients in various series has been >50 years, [1],[3],[4],[10] except in one series where the median age was 20.5 years. [2] The median age of our patients was 46 years, which is similar to most series. The older age of incidence is probably due to the incidence of AML per se later on in life.

There was no sex predominance in our study; however, the sex distribution of this illness is probably more in males as seen from the case series by Soupir et al. and Jameel et al.

The history of presenting illness was of short duration with no preceding chronic disease, suggestive of de novo AML rather than CML in blast crisis.

Of our four patients, three had mild to moderate splenomegaly. This is in concordance with other studies which reported no (1-5) or only mild to moderate splenic enlargement if at all.

The median WBC count was 54,000 cells/cumm, with median blasts of 43% in our series. This is variable in various series with median counts ranging from 19,100/cumm to >1 lakh/cumm. [1],[2],[3],[4],[5]

No basophilia was detected in our patients. This is as in other reported case series with lower incidence of basophilia with this entity. [1],[2],[4],[5]

Only two of our patients revealed additional cytogenetic abnormalities consistent with the evidence that additional abnormalities are less likely in Ph+ AML than in CML-in blast crisis. [3],[6],[10],[11],[12],[13] In addition, the marrow cytogenetic abnormalities seen were not those commonly seen in CML-blast crisis such as an additional Ph, trisomy 8, trisomy 19, or isochromosome 17q, [13],[14] suggesting that these are cases of de novo AML. Studies have been unable to identify recurrent abnormalities characteristic of Ph+ AML. [1],[3]

There was no particular FAB-subtype of AML that was more prevalent in our study; however, the FAB-subtypes associated, i.e., M2 and M0 are the ones that were more common in the largest case series reported by Supior et al. [1] and also Cuneo et al. [3] and Paietta et al. [6] Whether these subtypes are more prevalent in Ph+ AML need to be confirmed with larger series. With AML-M2 being the most common subtype of AML, concluding that Ph positivity is more common in them would be erroneous without further studies.

The transcript to detect the breakpoint cluster region could not be done at our center due to financial constraints. The series by Supior et al. [1] however found a majority of their cases with p210 BCR-ABL protein rather than p190 which is more common in Ph+ acute lymphoblastic leukemia. Since all patients had a short history, mild splenomegaly, lack of basophilia, with no cytogenetic abnormalities seen in those with CML-in blast crisis and had loss of Ph+ positivity following induction chemotherapy, it would be appropriate to say that all these are cases of Ph+ AML and not of CML in blast crisis.

The largest case series of Ph+ AML by Soupir et al. [1] reported four of their cases with preceding MDS; none of our patients had such history. None of our patients had developed extramedullary disease or relapse as reported by Amor et al. [4] whose patient developed meningeal relapse 19 months after diagnosis. Extramedullary disease in these patients has rarely been reported in world literature.

Three of the four patients who received standard induction chemotherapy were in remission after the first induction. One patient expired and two continue to be in remission. All our patients were initiated to and continued at a dose of 400 mg/day of tablet imatinib and no patient developed intolerance to the drug. The patient who expired, though was poorly tolerant to chemotherapy, tolerated imatinib well. Hence, the dose of 400 mg/day although lesser than the dose recommended for blast crisis seems to be successful in maintaining remission. Various studies have used higher doses of imatinib - 600 mg [4] and 800 mg/day [5] and demonstrated remission in these patients with imatinib alone. [4],[7]

Complete response to induction chemotherapy in patients with Ph+ AML has shown conflicting results in various studies. Some have shown encouraging [1],[3] while others have shown disappointing results. [2],[5],[6] Due to shorter duration of complete response, consolidation plays an important role in treatment. Studies have shown that allogeneic hematopoietic stem cell transplantation (HSCT) done in those following induction has shown a remission duration more than 2 years. [7],[15] In transplant ineligible patients, tyrosine kinase inhibitors (TKIs) have been used for consolidation and as maintenance after consolidation with high-dose Ara-C, and the outcomes were superior. [7] Role of reduced intensity conditioning regimen allogeneic HSCT is evolving. A lower survival among our patients could probably be explained since none of our patients underwent stem cell transplantation; however, one of our patients was in remission for 27 months possibly attributable to imatinib. The use of second-line TKIs such as dasatinib has been reported with a case report by Ritchie et al. demonstrating remission in a patient who relapsed after allogeneic stem cell transplant. [16] However, no studies are available with data on routine use and outcomes with second-generation TKIs in Ph+ patients. In the era of TKI, direct comparison between allogeneic HSCT and high-dose Ara-C as mode of consolidation is required. However, it is difficult to do so due to the rarity of this entity.

  Conclusion Top

Ph+ AML is a rare entity with no clear treatment recommendations. The improved outcomes with TKIs and allogeneic stem cell transplant for those patients in remission should prompt further studies with use of the second-generation TKIs and transplantation to develop treatment guidelines in this set of patients. If patients are in remission with long-term TKI use, it could serve as an alternative to stem cell transplantation in low-income countries with limited resources.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Soupir CP, Vergilio JA, Dal Cin P, Muzikansky A, Kantarjian H, Jones D, et al. Philadelphia chromosome-positive acute myeloid leukemia: A rare aggressive leukemia with clinicopathologic features distinct from chronic myeloid leukemia in myeloid blast crisis. Am J Clin Pathol 2007;127:642-50.  Back to cited text no. 1
Jameel A. Philadelphia chromosome positive acute myeloid leukemia: A rare hematological disorder: A case report. J Postgrad Med Inst 2012;26:111-4.  Back to cited text no. 2
Cuneo A, Ferrant A, Michaux JL, Demuynck H, Boogaerts M, Louwagie A, et al. Philadelphia chromosome-positive acute myeloid leukemia: Cytoimmunologic and cytogenetic features. Haematologica 1996;81:423-7.  Back to cited text no. 3
Ben Amor IB, Mseddi SH, Kassar O, Mnif S, Jdidi I, Mdhaffar M, et al. Philadelphie chromosome-positive de novo acute myeloid leukemia. Isolated meningeal relapse in a patient treated with imatinib mesylate. Case Rep Clin Med 2013;2:167-9.  Back to cited text no. 4
Yip SF, Wan TS, Liu HS, Wong ML, So CC, Chan LC. Philadelphia chromosome unmasked as a secondary genetic change in acute myeloid leukemia on imatinib treatment. Leukemia 2006;20:2050-1.  Back to cited text no. 5
Paietta E, Racevskis J, Bennett JM, Neuberg D, Cassileth PA, Rowe JM, et al. Biologic heterogeneity in Philadelphia chromosome-positive acute leukemia with myeloid morphology: The eastern cooperative oncology group experience. Leukemia 1998;12:1881-5.  Back to cited text no. 6
Reboursiere E, Chantepie S, Gac AC, Reman O. Rare but authentic Philadelphia-positive acute myeloblastic leukemia: Two case reports and a literature review of characteristics, treatment and outcome. Hematol Oncol Stem Cell Ther 2015;8:28-33.  Back to cited text no. 7
Atfy M, Al Azizi NM, Elnaggar AM. Incidence of Philadelphia-chromosome in acute myelogenous leukemia and biphenotypic acute leukemia patients: And its role in their outcome. Leuk Res 2011;35:1339-44.  Back to cited text no. 8
Keung YK, Beaty M, Powell BL, Molnar I, Buss D, Pettenati M. Philadelphia chromosome positive myelodysplastic syndrome and acute myeloid leukemia-retrospective study and review of literature. Leuk Res 2004;28:579-86.  Back to cited text no. 9
Konoplev S, Yin CC, Kornblau SM, Kantarjian HM, Konopleva M, Andreeff M, et al. Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia. Leuk Lymphoma 2013;54:138-44.  Back to cited text no. 10
Cortes J, O′Dwyer ME. Clonal evolution in chronic myelogenous leukemia. Hematol Oncol Clin North Am 2004;18:671-84.  Back to cited text no. 11
Przepiorka D, Thomas ED. Prognostic significance of cytogenetic abnormalities in patients with chronic myelogenous leukemia. Bone Marrow Transplant 1988;3:113-9.  Back to cited text no. 12
Rowley JD. Ph 1-positive leukaemia, including chronic myelogenous leukaemia. Clin Haematol 1980;9:55-86.  Back to cited text no. 13
Khorashad JS, Deininger MW. Selection of therapy: Rational decisions based on molecular events. Hematol Oncol Clin North Am 2011;25:1009-23, vi.  Back to cited text no. 14
Bhatt VR, Akhtari M, Bociek RG, Sanmann JN, Yuan J, Dave BJ, et al. Allogeneic stem cell transplantation for Philadelphia chromosome-positive acute myeloid leukemia. J Natl Compr Canc Netw 2014;12:963-8.  Back to cited text no. 15
Ritchie DS, McBean M, Westerman DA, Kovalenko S, Seymour JF, Dobrovic A. Complete molecular response of e6a2 BCR-ABL-positive acute myeloid leukemia to imatinib then dasatinib. Blood 2008;111:2896-8.  Back to cited text no. 16


  [Table 1], [Table 2]

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