Introduction
Chronic myeloid leukemia is a myeloproliferative disease that is characterized by the presence of translocation t(9;22), known as the Philadelphia chromosome. The consequence of this translocation is the production of BCR-ABL1 fusion oncogene(1) which gives to the hematopoietic stem cells a proliferative advantage and a capacity of aberrant differentiation, the final result being represented by the expansion of myeloid compartment(2).
Chronic myeloid leukemia consists of three phases: chronic, accelerated and blast phase. The majority of patients present in the chronic phase, and the main symptoms are related to anemia and splenomegaly. The patients may be asymptomatic or may present systemic symptoms such as fatigue, weight loss, excessive night sweats or malaise. Most of the patients evolve into an accelerated phase prior to the blast phase, but in 20% of cases it is possible to transition into the blast phase without any warning signs (worsening constitutional symptoms, fever, infections or bleeding).
Chronic myeloid leukemia blast phase presents as an acute leukemia – in most cases, the acute leukemia is one of myeloid line, but in 30% of the cases it can present as acute lymphoblastic leukemia(3). Even though the majority of cases of chronic myeloid leukemia present as a B-cell lymphoblastic crisis, there are rare cases in which it could present as T-cell lymphoblastic crisis.
The diagnosis of chronic myeloid leukemia is suspected in the case of a patient with persistent and unexplained leukocytosis and important splenomegaly and it is documented by the presence of the Philadelphia chromosome – translocation t(9;22) – using fluorescence in situ hybridization (FISH) or the detection of BCR-ABL1 anomalies by molecular exam. The blast phase of the disease is diagnosed by the presence of at least 20% of blasts in the medullary aspirate or in the peripheral blood; the flow cytometry examination helps in finding out the blast cell lineage (B-cell/T-cell).
The management of the patient depends on the phase and on the disease prognosis; we can only use tyrosine kinase inhibitors in the chronic phase of the disease or tyrosine kinase inhibitors associated with intensive chemotherapy followed by allogeneic hematopoietic stem cell transplant in the more advanced phases of chronic myeloid leukemia. Even though the combination of tyrosine kinase inhibitors and intensive chemotherapy followed by stem cell transplantation seems to have the best outcome, the overall cure rates are in the range of 10-20%.
In cases of chronic myeloid leukemia presenting as lymphoblastic phase, when patients have never been treated with tyrosine kinase inhibitors, the treatment should be the same as that given to patients with de novo Philadelphia positive acute lymphoblastic leukemia(3).
Case presentation
In December 2019, a 46-year-old patient, kidney donor and with a history of pulmonary tuberculosis, came to the emergency department of our hospital for pain in the left abdominal quadrant. The pain had started two weeks prior to the consult and increased gradually. He had no history of fever, night sweats or weight loss.
The clinical exam revealed both hepatomegaly and splenomegaly. The laboratory tests from the emergency department revealed important leucocytosis (approximately 300,000/mmc) without anemia, thrombocytopenia or changes in biochemical parameters. The abdominal ultrasonography highlighted hepatomegaly (approximately 180 cm) and a massive splenomegaly (approximately 200 cm). The pulmonary radiography showed old changes in both lungs due to tuberculosis and also small left pleural effusion. The eye fundus examination was without bleeding or exudate.
The patient was hospitalized for further investigations in order to establish the diagnosis, the prognosis and the optimal treatment. We suspected a case of chronic myeloproliferative disease at diagnostic.
The peripheral blood smear showed a left deviated formula until blast (8% blasts), with neutrophilia, eosinophilia and basophilia. We tried to perform a medullar aspiration from the posterior-superior iliac crest, but without success, so we decided to perform an osteomedullary biopsy. We also requested a flow cytometry exam, a fluorescence in situ hybridization exam and a molecular exam (detection of transcript BCR-ABL1), all of them from the peripheral blood.
Because all the laboratory investigations that we performed took some time until we got the results and the clinical condition of the patient began to deteriorate (he started to develop fever without any signs of infection), we decided to try to perform another medullar aspiration, this time from the sternum. The results revealed a hypercellular medular aspiration with 68% blasts without definite morphological aspects.
Both flow cytometry and osteomedullar biopsy revealed the diagnosis of acute lymphoblastic leukemia with B line cells, CALLA positive, and maybe Philadelphia chromosome positive. The fluorescence in situ hybridization exam showed the translocation t(9;22) in 100% of the examined cells and the molecular exam revealed the transcript BCR-ABL1 b2a2 that corresponds to the p210 protein. No mutations were found in the kinase domain of BCR-ABL1 gene (codons 252-450).
We faced a challenging diagnosis and we had to make the differential diagnosis between acute B-cell lymphoblastic leukemia, CALLA positive, Philadelphia chromosome positive or chronic myeloid leukemia presenting as a B-cell lymphoblastic crisis. Due to the fact that the patient had a peripheral blood smear with left deviated formula until blast, with neutrophilia, eosinophilia, basophilia and important splenomegaly, the translocation t(9;22) being present in 100% of the analyzed cells and the transcript BCR-ABL1 b2a2 that corresponds to the p210 protein was present, we established the diagnosis of chronic myeloid leukemia presenting as a B-cell lymphoblastic crisis. The Sokal and EUTOS long-term survival (ELTS) scores framed the patient in a high-risk category.
While we were waiting for the results of the investigation, we started the cytoreductive treatment (Hydrea® 1000 mg twice daily), the uricosuric treatment (allopurinol 100 mg twice daily) and the parenteral hydration.
We had to decide the best option of treatment. Prior to chemotherapy we performed an infectious screening that was negative, an echocardiography which revealed a left ventricular ejection fraction of about 67%, 5 mm of pericardial effusion, and we also did a magnetic resonance imaging of the brain to find out if there is any infiltration of the disease in the central nervous system, but there wasn’t. The patient was a candidate for allogeneic hematopoietic stem cell transplantation and we performed the HLA typing and the searching of a matching donor.
We decided that the optimal treatment should be the GRAAPH-2005 protocol associated with imatinib 800 mg daily (day 1 to 28), according to the national guideline and the international references. We chose imatinib because the patient already had pleural and pericardial effusion before starting the treatment.
The first cycle of treatment (vincristine 2 mg on days 1, 8, 15 and 22, dexamethasone 40 mg on days 1-2, 8-9, 15-16 and 22-23, and imatinib 800 mg daily from day 1 to day 28) was relatively well tolerated, and the period of post-chemotherapy aplasia was overcome with granulocyte growth factor, irradiated transfusion of both erythrocyte mass and platelet concentrate, broad-spectrum prophylactic antibiotic therapy and prophylactic antiviral therapy. The prophylactic intrathecal administration of chemotherapy (methotrexate 15 mg, Cytosar® 40 mg, and dexamethasone 4 mg) was skipped due to the presence of peripheral blasts on day 1, and then on day 8, due to the important thrombocytopenia, but the intrathecal administration of chemotherapy was done on day 15. The evolution of the patient was quite good and we were preparing the file for allogeneic transplantation.
The second cycle of treatment consisted of methotrexate 1,900 mg on day 1, Cytosar® 5,700 mg twice daily on days 2 and 3, imatinib 800 mg daily, and prophylactic intrathecal administration of chemotherapy on day 1. After methotrexate administration, we gave to the patient calcium folinate according to the administration schedule. The patient also received granulocyte growth factors, broad-spectrum prophylactic antibiotic therapy, and both antiviral and antifungal prophylactic therapy.
On the 10th day, the patient started to develop fever, twice daily, but the fever episodes increased gradually on the following days, even though we gave him ultra-wide-spectrum antibiotic therapy and the infectious screening was negative. Four days after, the patient’s condition began to deteriorate, he was permanently feverish despite antipyretics, he started to cough, his blood pressure dropped, the oxygen saturation reached the level of 70% with oxygen on the facial mask, and he was admitted to the intensive care unit. Unfortunately, the patient died and the result of the sputum exam which was available after his death revealed the presence of the multidrug-resistant Acinetobacter.
Discussion
Nowadays, for the treatment of chronic myeloid leukemia presenting as B-cell lymphoblastic crisis, we use tyrosine kinase inhibitors combined with intensive chemotherapy, followed by allogeneic stem cell transplantation, according to international recommendations(4), but the overall cure rates are very low. This intensive treatment is associated with high rates of myelosuppression and induction deaths(5), thus the management of the advanced phase of chronic myeloid leukemia is still challenging, despite the improved treatment options over the years.
Our patient was young and tyrosine kinase inhibitor-naïve, therefore the protocol of treatment should be the same as the one chosen for de novo Philadelphia positive acute lymphoblastic leukemia(3). We decided that the best treatment option would be GRAAPH-2005 protocol in association with imatinib.
The reason why we chose GRAAPH-2005 protocol, a lower intensity therapy, despite hyper-CVAD regimen, was due to the fact that GRAAPH-2005 protocol has less early mortality, a higher rate of hematologic complete remission, non-inferior rates of overall survival and event-free survival at five years(6).
As for the tyrosine kinase inhibitor, we chose imatinib despite other tyrosine kinase inhibitors (for example, dasatinib), because we took into account the side effects of this drug(7), our patient having pleural and pericardial effusion before starting any treatment. Moreover, there was no mutation found in the kinase domain of BCR-ABL1 gene.
For patients with de novo blast phase of chronic myeloid leukemia, allogeneic transplantation is recommended in all cases when the patient is a candidate for transplantation(5) after returning to the chronic phase of the disease with the optimal treatment. Our patient was an ideal candidate for allogeneic transplantation: he had no significant comorbidities, no active infections, and no psychiatric issues. The medullary aspiration performed before the start of the second cycle of treatment of the GRAAPH-2005 protocol was without blast infiltration.
Unfortunately, the allogeneic transplantation could not be performed because the patient died of sepsis due to multidrug resistant Acinetobacter on the fifteenth day of the second cycle of treatment with the GRAAPH-2005 protocol.
This case report presents the evolution of a young patient with an advanced stage of chronic myeloid leukemia at diagnosis who was treated with a lower intensity therapy due to the concern of high rates of myelosuppression and induction death caused by more intense chemotherapy, and who, despite this option and the use of ultra-wide-spectrum antibiotic therapy, died of sepsis with multidrug resistant Acinetobacter.
Conclusions
Chronic myeloid leukemia presenting as B-cell lymphoblastic crisis has a small percentage of cure, even though we add to the treatment with tyrosine kinase inhibitors intensive chemotherapy and allogeneic hematopoietic stem cell transplant.
The important part of this case presentation is the fact that the patient was asymptomatic for a long period, he started to feel pain in the left abdominal quadrant two weeks before the presentation to the hospital, he was diagnosed with chronic myeloid leukemia B cell lymphoblastic crisis at the first presentation in the hospital, he did not have significant comorbidities, and he was an ideal candidate for allogeneic hematopoietic stem transplantation.
Even though the patient was treated according to the GRAAPH-2005 protocol, chosen over hyper-CVAD regimen, due to the similar benefits but with less toxicity, he presented an unfavorable evolution, dying of sepsis with multidrug-resistant Acinetobacter on the fifteenth day of the second cycle of treatment with the GRAAPH-2005 protocol.
This case is a very good example for understanding the sensitivity of the hemato-oncological patients and their predisposition to severe infections even in the presence of ultra-wide-spectrum antibiotic therapy and in the absence of any significant comorbidities.