Philadelphia Chromosome-positive Acute Myeloid Leukemia Research Articles

Prognostic Factors in Philadelphia Chromosome-Positive Acute Myeloid Leukemia Using Fluorescence in Situ Hybridization.

Philadelphia chromosome-positive acute myeloid leukemia (Ph+ AML) is a rare leukemia subtype first classified by the World Health Organization in 2016. The incidence of Ph+ AML is approximately 0.5 - 3%, and its prognosis is poor. Ph+ AML with additional chromosomal abnormalities in children has rarely been reported, and its treatment and prognosis remain uncertain. We retrospectively analyzed 649 patients with AML from 2006 - 2021. Six (0.9%) patients with Ph+ AML were identified and treated with conventional chemotherapy. The clinical features and prognoses were retrospectively analyzed. Six cases of AML with a Ph chromosome were reported. One of the six individuals exhibited a biphenotypic immunophenotype, one exhibited a simple myeloid immunophenotype, and the other four exhibited myeloid and lymphoid expression. Karyotypic analysis (R banding) was performed in six cases, four of which were classical Ph chromosomal abnormalities, two of which had additional abnormalities outside the Ph chromosome. Fluorescence in situ hybridization (FISH) analysis using the BCR/ABL fusion gene distinguished that the BCR major breakpoint break in three cases was type P210 and the BCR minor breakpoint break in three cases was type P190. The complete remission rate of the six patients in this study using conventional chemotherapy was 60%, with a median survival time of 7.5 months. In summary, Ph+ AML is a heterogeneous disease often associated with additional chromosomal abnormalities. Ph+ AML is seen with a lymphoid immunophenotype and alterations in associated genes such as the IGH gene. Adults were predominantly P210 and two cases in children were both P190. Conventional treatments are less effective, and there are no standard treatment regimens.

Olverembatinib (HQP1351) Combined with Chemotherapy Is an Effective and Safe Treatment in Patients with Philadelphia Chromosome-Positive (Ph +) Acute Lymphoblastic Leukemia (ALL) and Chronic Myeloid Leukemia in Lymphoid Blast Phase (CML-LBP) That Failed TKI-Based Regimens

Background The prognosis of relapsed or refractory (R/R) Philadelphia Chromosome-Positive (Ph+) acute lymphoblastic leukemia (ALL) and TKI-resistant chronic myeloid leukemia in lymphoid blast phase (CML-LBP) remains poor, with lower rates of complete remission (CR) and shorter durations of response. Olverembatinib is a novel third-generation tyrosine kinase inhibitor (TKI) that has been demonstrated to effectively target a wide range of BCR::ABL1 kinase mutations, especially T315I, in patients with CML in the chronic or accelerated phase resistant to either imatinib or second-generation TKIs. However, data on olverembatinib-based regimens in R/R Ph+ ALL and CML-LBP are limited. Here, we report the efficacy and safety of olverembatinib, combined with chemotherapy, in patients with Ph+ ALL or CML-LBP that failed prior TKI-based therapies. Methods A retrospective study was conducted in adults with Ph + ALL or CML-LBP who failed imatinib- or second-generation TKI-based chemotherapy and subsequently received olverembatinib-based chemotherapy. Per NCCN 2023 guidelines: refractory disease was defined as CR not achieved at the end of induction; relapsed disease, reappearance of blasts in the blood or bone marrow (> 5%) or any extramedullary site after CR; molecular resistance, persistent or rising BCR::ABL1 transcript (> 1-log) by real-time quantitative polymerase chain reaction (RT-qPCR); and complete molecular response (CMR), BCR::ABL1 transcript < 0.01% by RT-qPCR. The primary endpoints of this study were CR rates in R/R patients and CMR rates in molecular-resistant patients. Results From February 2022 to May 2023, 31 patients were included in this study, including 24 (77%) with TKI-based chemotherapy-failed Ph + ALL; 7 (23%) with TKI-resistant CML-LBP; 15 (48%) with R/R disease; and 16 (52%) with molecular-resistant disease. A total of 17 (57%) patients were male, and the median (range; IQR) age was 46 (20-72; 30-64) years. Among 30 patients screened for BCR::ABL1 kinase domain mutations before administration of olverembatinib, 6 (19%) had no mutations; 15 (48%) had T315I; and 9 (29%) had other mutations, including E255K (n = 2), G250E(n = 2), D241E (n = 1), Y253H (n = 1), F317L (n = 1), F359C(n = 1), and Y253Fplus M351T (n = 1). The 15 R/R patients (11, Ph + ALL; 4, CML-BP) received olverembatinib 30 or 40 mg on alternate days combined with VP (vindesine 4 mg once per week for 4 weeks and prednisone 1 mg/kg for 3 weeks and tapered at the fourth). A total of 13 (86%) patients achieved CR after 4-week induction therapy. At a median (IQR) follow-up of 8 (4-13) months, 5 patients received allogeneic transplantation in CR, and were alive in CMR. A total of 8 patients received olverembatinib-based consolidation chemotherapy of either VP (n = 4) or hyper-CVAD (n = 4) after achieving CR. Six patients relapsed, of whom 4 died, and 1 remained in CMR. The 1-year relapse-free survival (RFS) and 1-year survival rates were 52% (95% CI, 21-83) and 68% (95% CI, 37-98), respectively. Among the 16 patients with molecular resistance to TKI-based chemotherapy (imatinib [n = 4]; dasatinib [n = 9]; flumatinib [n = 3]), 2 received olverembatinib monotherapy, 7 olverembatinib plus VP, and 7 hyper-CVAD, of whom 8 received subsequent allogeneic transplantation. At a median (IQR) follow-up of 9 (5-11) months, 1 of the patients receiving olverembatinib monotherapy progressed to hematologic relapse and was switched to CAR T-cell therapy; the other patient did not achieve CMR and underwent transplantation. Of the 14 patients receiving olverembatinib plus chemotherapy, 7 (50%) achieved CMR and 3 (21.4%) progressed to relapse, of whom 1 had hematological relapse and 2 developed central nervous system leukemia (CNSL) with bone marrow remission. A total of 7 patients received allogeneic transplantation, of whom 3 achieved and 4 did not achieve CMR before transplantation. After transplantation, all the 7 patients were in CMR except one who developed CNSL. The 1-year RFS and survival rates were 67% (95% CI, 42-91) and 93% (95% CI, 79-100), respectively. Among all patients, hematologic adverse events were readily manageable. Treatment-related nonhematologic severe adverse events were observed in 3 patients, including (each) stable angina pectoris, severe pneumonia, and fatal Klebsiella sepsis. Conclusions Olverembatinib-based chemotherapy is effective and safe in patients with R/R and molecular resistant Ph + ALL or CML-LBP.

Flumatinib plus venetoclax as an effective therapy for Philadelphia chromosome‐positive acute myeloid leukemia: A case report

Philadelphia chromosome-positive acute myeloid leukemia (Ph + AML) is a rare type of AML with a low survival rate and poor prognosis. We first report a Ph + AML patient who remained in long-term remission after the combination of flumatinib and venetoclax, which could provide corresponding treatment ideas for clinical practice.

Long-Term Follow-up on Adult Patients with Philadelphia-Chromosome Positive Acute Myeloid Leukemia Who Were Treated with Interim Imatinib Followed By Allogeneic Hematopoietic Cell Transplantation

▪Background: The incidence of Philadelphia chromosome (Ph)-positivity in adult patients with acute myeloid leukemia (AML) is very low ranging from only 1 to 2%. Ph-positive AML has been included in the high-risk group presenting lower complete remission (CR) rate and early relapse after standard chemotherapy. However, the treatment outcome in a large cohort is not well elucidated due to its low incidence and variable treatment strategies including the use of tyrosine kinase inhibitors. We attempted to unveil clinical outcomes of Ph-positive AML in association with concomitant chromosomal abnormalities.Methods: We retrospectively analyzed 29 patients with Ph-positive AML (median age: 43 years old [range; 18-80]) from 2002 to 2016. Except for the 2 patients who did not get treated at all, 3 were treated repeatedly with low-dose cytarabine and 24 were treated with 3+7 standard induction chemotherapy, followed with the application of interim imatinib 400mg until the starting day of next chemotherapy or conditioning for hematopoietic cell transplantation (HCT). Among them, 17 underwent allogeneic HCT from sibling donors (n=6), unrelated donors (n=7), and haploidentical donors (n=4).Results: In total of 29 patients, 7 (24.1%) had additional inv(16). There were 3 therapy-related AML in Ph-positive AML subgroup with inv(16), while none were observed in the subgroup without inv(16). In the Ph-positive AML subgroup with inv(16), median age was younger (31 vs. 44 years old, p= 0.083) and CR rate was higher (85.7% vs. 54.5%, p= 0.214) than the opposite. Among 27 treated patients, 20 (74.1%) patients achieved CR after standard chemotherapy with interim imatinib, and 2 achieved CR after low-dose cytarabine with interim imatinib. In the entire patients group, after a median follow-up duration of 41.5 months (range: 0.2 to 156.6), 5-year overall survival (OS) was 40.1%. However, 5-year OS of 17 patients (11 in subgroup without inv(16) and 6 in subgroup with inv(16)) treated with allogeneic HCT was 69.3%, and 6 patients among them with Ph-positive AML with inv(16) were all alive after allogeneic HCT. In contrast, all 12 patients who were not treated with allogeneic HCT expired within a median of 6.3 months [range: 0.2-18].Conclusion: This study revealed that interim imatinib combined chemotherapy produced an acceptable CR rate, and allogeneic HCT as a post-remission therapy was a feasible choice for providing a long-term disease control in adult patients with Ph-positive AML. We also identified that inv(16) was related to favorable outcomes regardless of the coexisting t(9;22) and to therapy-related AML. DisclosuresKim:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Allogeneic hematopoietic cell transplantation efficacy in patients with Philadelphia chromosome-positive acute myeloid leukemia in complete remission.

Philadelphia chromosome-positive acute myeloid leukemia (Ph+ AML) confers a dismal prognosis when treated with chemotherapy alone. Data on allogeneic hematopoietic cell transplantation (allo-HCT) outcomes are limited. We retrospectively analyzed 4649 AML patients who received allo-HCT and were in complete remission. Outcomes of Ph+ AML (n = 30), intermediate-risk, and poor-risk AML patients were compared. The 3-year overall survival after allo-HCT was similar in intermediate-risk (62.7%; 95% CI: 61.0-64.3%) and Ph+ AML (73.3%; 95% CI: 51.5-86.4%) groups (P = 0.42); however, it differed significantly between the poor-risk (49.7%; 95% CI: 45.9-53.4%) and Ph+ AML (73.3%; 95% CI: 51.5-86.4%) groups (P = 0.049). Disease-free survival in Ph+ AML patients was comparable to that in intermediate-risk patients but better than that in poor-risk patients. Relapse rates were significantly lower in Ph+ AML patients than in other groups. Non-relapse mortality (NRM) rates were similar among groups. Multivariate analysis showed that Ph+ AML was not a significant predictor of poor prognosis in terms of overall survival, disease-free survival, relapse, and NRM. Our data showed better post-transplant outcomes for Ph+ AML patients than for those with poor-risk AML. Hence, allo-HCT could be a feasible treatment option for Ph+ AML patients.

T-lymphoblastic lymphoma complicated with Philadelphia chromosome-positive acute myeloid leukemia: report of one case and review of literature

目的 探讨T淋巴母细胞淋巴瘤（T-LBL）伴费城染色体阳性急性髓系白血病（Ph+ AML）的诊治方法。 方法 回顾性分析靖江市人民医院收治的1例T-LBL伴Ph+ AML患者的临床表现、遗传学检查、组织病理结果、治疗经过，并进行文献复习。 结果 该患者为目前鲜见报道的成年人T-LBL伴Ph+ AML，初期病理切片荧光原位杂交（FISH）检测提示BCR-ABL融合基因阳性。患者T-LBL确诊后予以淋巴瘤方案化疗有效，但在第3个疗程骨髓恢复期继发Ph+ AML，予以羟基脲口服及白细胞单独采集，但疾病进展迅速，患者短期内死亡。 结论 T-LBL伴Ph+ AML非常罕见，谱系转换的机制目前尚不清楚。可表现为相继发病，来源相同。

Allogeneic Stem Cell Transplantation in Patients with Philadelphia Chromosome-Positive Acute Myeloid Leukemia in Japan

Allogeneic Stem Cell Transplantation in Patients with Philadelphia Chromosome-Positive Acute Myeloid Leukemia in Japan

Venetoclax (VEN) and tyrosine kinase inhibitor (TKI) combinations in Philadelphia chromosome-positive (Ph+) acute myeloid leukemia (AML) and chronic myeloid leukemia myeloid blast phase (CML MBP).

e18515 Background: Ph+ AML and CML MBP have poor outcomes. VEN synergizes with BCR-ABL TKIs in vitro and may eradicate Ph+ leukemic stem cells. However, the clinical activity of VEN+TKI regimens is unknown. Methods: We conducted a retrospective study on patients (pts) with Ph+ AML and CML MBP who received regimens with VEN+TKI at our institution. Results: We identified 6 pts with relapsed/refractory (R/R) Ph+ AML and 7 with CML MBP (2 transformed from chronic phase, 5 R/R). 10 pts (77%) were refractory to prior therapy and 3 (23%) had relapsed disease. Pt characteristics are shown in the Table. 5 AML pts (83%) had complex cytogenetics. Pts with CML MBP had received a median of 2 prior TKIs (range 1-3). 7 pts received decitabine-based combinations and 6 pts received intensive chemotherapy in combination with VEN+TKI. TKIs included ponatinib (n=7), dasatinib (n=4), bosutinib (n=1) and nilotinib (n=1). Among 12 evaluable pts, the overall response rate (CR + CRi + MLFS) was 50% (Table). In addition, 1 pt with AML developed aplastic marrow, underwent stem cell transplantation, and is still alive. Pts with CR/CRi vs. those without CR/CRi had higher median number of Ph+ metaphases (100% vs. 32%, p<0.01) and higher baseline BCR-ABL1 PCR (100% vs. 0.5% p=0.01). The only AML pt who achieved CR/CRi had 100% Ph+ metaphases. After a median follow-up of 10.9 months (mo), 5 pts are alive (1 AML, 4 CML MBP). The median overall survival for pts with AML and CML MBP were 2 mo and not reached, respectively. The median relapse-free survival was 8.2 mo. Conclusions: VEN+TKI combinations show encouraging activity in pre-treated, advanced Ph+ leukemias, particularly CML MBP. Clonal burden of Ph+ cells correlated with response. Prospective trials are needed to evaluate VEN+TKI combinations in Ph+ leukemias. Pt characteristics and outcomes (n/N [%] / median [range]). [Table: see text]

Impact of an Additional Chromosome on the Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Philadelphia Chromosome–Positive Acute Myeloid Leukemia in Adults

The incidence of Philadelphia chromosome positivity (Ph+) in adults with acute myeloid leukemia (AML) is very low. Ph+ AML is considered to be high risk for failure to attain remission or for early relapse after standard chemotherapy. Because of the low incidence of the disease, it has been difficult to determine the best treatment, including the effects of tyrosine kinase inhibitors. We retrospectively analyzed 29 patients with Ph+ AML (median age, 45 years; range, 18 to 80) managed at our center between 2002 and 2016. Two patients were not treated at all, 3 received repeated low-dose cytarabine, and 24 were treated with 3 + 7 standard induction chemotherapy. All 27 treated patients also received interim imatinib 400 mg orally until the day of the next chemotherapy cycle began or as conditioning for allogeneic hematopoietic cell transplantation (HCT), which was performed in 17 patients. Of the 29 patients with Ph+ AML, 7 (24.1%) had additional inv(16), 3 of whom had therapy-related AML. In the 7 with inv(16), the median age was younger (31 versus 44 years, P = .083) and the complete remission (CR) rate was relatively higher (85.7% versus 54.5%, P = .214) than in those without inv(16). Among the 27 treated patients, 20 (74.1%) achieved CR after standard chemotherapy with interim imatinib and 2 (7.4%) achieved CR after low-dose cytarabine with interim imatinib. After a median follow-up of 65.5 months (range, 13.4 to 156.6), the 5-year overall survival (OS) among all 27 treated patients was 43.1%. For the 17 patients who underwent HCT the 5-year OS of 17 patients (10 in subgroup without inv(16) and 7 in subgroup with inv(16)) treated with allogeneic HCT was 69.3%. All 7 with inv(16) were still alive at the end of the study. In contrast, all patients not treated with HCT died within a median of 6.25 months (range, .2 to 18.2). Interim imatinib combined with chemotherapy yielded an acceptable remission rate in adult patients with Ph+ AML. Allogeneic HCT as a postremission therapy provided long-term disease control in two-thirds of those who underwent the transplant. We also demonstrated that inv(16) was related to a favorable outcome in Ph+ AML, including therapy-related AML.

Oncogenic Feedback Activation Between BCL6 and MLL Promotes Malignant Transformation in MLL-RearrangedAcute Lymphoblastic Leukemia

Background:BCL6 is known as a protooncogene and transcriptional repressor in diffuse large B cell lymphoma, where it is frequently involved in chromosomal rearrangements. We recently identified BCL6 as a novel mediator of drug resistance to tyrosine kinase inhibitors (TKI) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (Duy et al., Nature 2011; Hurtz et al., J Exp Med 2011). In addition,BCL6 directly competes with the tumor suppressor BACH2 for p53 promotor binding to protecting cells from p53-mediated apoptosis in multiple ALL subgroups (Swaminathan et al., Nature Medicine 2013). Based on this, our current study is focusing on the function of BCL6 in different subtypes of human ALL.Results: Analysis of gene expression data from 207 children with high-risk B cell precursor ALL (COG P9906) showed that high expression levels of BCL6 at the time of diagnosis correlated with a poor overall and relapse-free survival (p=0.007). Furthermore, 49 matched sample pairs from patients at diagnosis and relapse showed increased BCL6 levels at relapse compared to diagnosis (p=0.003). To test whether or not there are specific subtypes of leukemia with high BCL6 expression levels, we studied BCL6 expression via western blot and immunohistochemistry staining in Non-Ph+ cell lines and ALL patient samples (n=76). Interestingly, BCL6 levels are particularly elevated in MLL-rearranged (MLLr) ALL cases. In addition, patients from the clinical trial that had high BCL6 levels and had MLL rearrangements had the worst clinical outcome (p=0.0009). We next tested if MLLr oncogenes drive aberrant BCL6 expression. First, we performed a ChIP-analysis using antibodies against MLL, AF4, and ENL, which provided evidence for direct binding to the BCL6 promoter. We then performed a BCL6 Western blot analysis of inducible MLL-AF4-transgenic and retrovirally transduced MLL-ENL pre-B cells, demonstrating that both oncogenes are sufficient to induce ~10-fold upregulation of BCL6 protein levels. Additionally, we used a newly developed conditional BCL6 knock out/reporter mouse model to decipher the function of BCL6. We transduced B cell progenitor cells from BCL6fl/fl mice with MLL-ENL and either with a control or Cre-expression vector. Using the BCL6 reporter capability of the mouse we found that BCL6 is significantly higher expressed in MLL-ENL transduced cells. To test if MLL is required for BCL6 upregulation, we used a conditional MLL knock out mouse and found that after Cre-mediated deletion of MLL, pro-B, mature-B, and MLL-AF4 transduced ALL cells almost lost the ability to upregulate BCL6. Interestingly, using inducible BCL6 transgenic and knockout as well as retrovirally transduced pre-B and ALL cells showed that overexpression of BCL6 leads to higher expression levels of MLL and deletion of BCL6 results in lower expression levels of MLL. Therefore, we conclude that MLL and BCL6 both cooperate and activate each other's expression in an activating feedback loop. Strikingly, Cre-mediated BCL6- deficiency results in apoptosis of MLL-ENL transduced cells.Clinical relevance: To verify if the high BCL6 expression levels in MLL-AF4 patients are important for the disease progression, we transduced primary human ALL xenografts with a dominant-negative BCL6-mutant (BCL6-DN). Expression of BCL6-DN rapidly induced cell cycle arrest and cell death. To test if pharmacological inhibition of BCL6 is of potential use for patients with MLLr leukemia, we treated multiple MLL-AF4 rearranged human xenograft cases with a RI-BPI a BCL6 peptide inhibitor. Strikingly, treatment with RI-BPI not only compromised colony formation in methylcellulose it also prevents leukemia-initiation in transplant recipient mice. RI-BPI also had a strong synergistic effect when combined with the chemotherapy drug Vincristine, which represents the backbone for most high risk regimen in pediatric ALL.Conclusions: These findings identify BCL6 as a central factor in leukemia initiation and survival and its pharmacological inhibition as a novel strategy to treat MLL-rearranged ALL. Aberrant expression of BCL6 in MLLr ALL is the direct consequence of the MLLr oncogenic activity in these cells. Based on these findings, we propose combinations of BCL6 inhibitors with currently used chemotherapeutics as potential approach to reduce the risk of ALL relapse and improve overall outcome. DisclosuresArmstrong:Epizyme, Inc: Consultancy. Ernst:Amgen: Other: stocks. Melnick:Janssen: Research Funding.

Characteristics and clinical outcome of T315I mutation in Philadelphia chromosome-positive acute lymphoblastic leukemia and chronic myeloid leukemia

目的分析伴T315I突变的Ph染色体阳性急性淋巴细胞白血病(Ph+ALL)和慢性髓性白血病(CML)的特征及疗效。方法收集2014年3月至2015年6月于郑州大学附属肿瘤医院行ABL激酶区突变检测并对酪氨酸激酶抑制剂(TKI)耐药的23例Ph+ ALL患者和95例CML患者的临床资料。采用R显带法进行染色体分析，实时定量PCR方法检测BCR-ABL融合基因，TRIzol法提取总RNA，直接测序法检测ABL激酶区突变。结果ABL激酶区突变发生率在TKI耐药Ph+ ALL和CML中分别为60.9%(14/23)、41.1%(39/95)，其中T315I突变发生率分别为34.8%(8/23)和5.3%(5/95)，差异具有统计学意义(χ2=13.586，P<0.01)。CML慢性期患者ABL激酶区突变发生率为38.8%(19/49)，加速期、急变期分别为47.1%(8/17)、41.4%(12/29)，差异无统计学意义(χ2=0.360，P=0.835)。Ph+ ALL、CML患者自开始TKI治疗至发生T315I突变的中位时间分别为10和19个月，T315I突变发生至死亡或随访终止的中位时间分别为2和3个月，中位血液学缓解持续时间分别为10和16个月，中位总生存时间分别为13和42个月。结论Ph+ ALL较CML更易出现T315I突变，但两者自开始TKI治疗至发生T315I突变的中位时间相近，在现有方案治疗下，两者血液学缓解持续时间、总生存时间相近。

Isolated central nervous system relapse in patient with blast-crisis chronic myeloid leukemia in durable complete cytogenetic remission on dasatinib treatment: pharmacokinetics and ABL mutation analysis in cerebrospinal fluid

Central nervous system involvement is a relatively common complication in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) and chronic myeloid leukemia in blast crisi...

Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia

Philadelphia chromosome-positive (Ph+) acute myeloid leukemia (AML) is a controversial diagnosis, as others propose that it represents chronic myelogenous leukemia in blast phase (CML-BP). NPM1 mutations occur in 25–35% of patients with AML but are absent in patients with CML. Conversely, ABL1 mutations occur in 25% of imatinib-naive patients with CML-BP but are not described in patients with AML. We analyzed for NPM1 and ABL1 mutations in nine Ph+ patients with AML and five patients with CML-BP initially presenting in BP. In six cases of Ph+ AML, we screened for a panel of gene mutations using Sequenome®-based methods including AKT1, AKT2, AKT3, BRAF, EGFR, GNAQ, GNAS, IDH1, IDH2, KRAS, MET, NRAS, PIK3CA and RET. Two of nine (22%) patients with Ph+ AML had NPM1 mutations and were alive 36 and 71 months after diagnosis. All cases of Ph+ AML were negative for ABL1 and other gene mutations. One (20%) patient with CML-BP had ABL1 mutation; no patients had NPM1 mutations. These data suggest that Ph+ AML is distinct from CML-BP.

Successful treatment of childhood Philadelphia chromosome–positive acute myeloid leukemia

Fig. S1 Acute myeloid leukemia-M5. Bone marrow smear shows several immature monocytoid cells with multiple prominent nucleoli and moderately abundant pale cytoplasm (Wright's stain). Fig. S2 Acute myeloid leukemia-M5. Bone marrow smear. Periodic acid-Schiff reaction. The cytoplasm of the monoblasts shows diffuse PAS staining. Fig. S3 Acute myeloid leukemia with t (9;22) (q34;q11). R banded karyotype showing 46 chromosomes, including t (9;22) (q34;q11). Fig. S4 Acute myeloid leukemia with t (9;22) (q34;q11). Metaphase fluorescence in situ hybridization using dual color probes BCR and ABL shows the presence of a BCR-ABL fusion. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Incidence of Philadelphia-chromosome in acute myelogenous leukemia and biphenotypic acute leukemia patients: And its role in their outcome

Background Philadelphia-chromosome positive acute myeloid leukemia (Ph+ AML) is a rare entity and patient prognosis is poor, with short median survival. Biphenotypic acute leukemia (BAL) is a rare disorder that is difficult to diagnose and it displays features of both myeloid and lymphoid lineage. The aim of this study was to highlight the incidence of Philadelphia chromosome and its presence in cases of acute myeloid and biphenotypic leukemia and determine its role in the outcome of these leukemias. Subjects and methods This study examined 464 subjects with newly diagnosed acute myeloid leukemia: 312 were males and 152 were females. All individuals were subjected to immunophenotyping and conventional karyotyping. FISH was used in failed cases of conventional cytogenetics analysis to quantify disease and to prove positive BCR-ABL fusion gene. Results the incidence of Ph+ chromosome was found to be higher in BAL (38.4%) than in AML (1.99%). There was statistically significant difference according to the age and the median survival time between the two groups. Conclusion Detection of specific chimeric transcripts in AML and BAL at the time of diagnosis was crucial since it plays an important role for accurate risk stratification and treatment management.

Loss of Philadelphia chromosome after graft failure following cord blood transplantation for Philadelphia chromosome-positive acute myeloid leukemia

Loss of Philadelphia chromosome after graft failure following cord blood transplantation for Philadelphia chromosome-positive acute myeloid leukemia

Imatinib Combined with Chemotherapy and Allogeneic Stem Cell Transplantation Results In Long Time Survival In Patients with De Novo Ph+ AML

AbstractAbstract 4368De novo Philadelphia chromosome-positive acute myeloid leukemia is a rare condition with a poor prognosis. Allogeneic stem cell transplantation (allo-SCT) is always recommended to treat this disease although its results are not always satisfactory even in young patients. Imatinib is a protein tyrosine kinase inhibitor that has now been shown to be active in Ph+ chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia, however its role in Ph+ AML has not been extensively investigated. We present two patients with de novo Ph+ AML who received Imatinib combined with chemotherapy and allogeneic stem cell transplantation (allo-SCT), followed by Imatinib maintainance treatment after allo-SCT. These patients achieved long-term disease-free survival for 34 and 44 months respectively. Patient 1: A 19-year-old woman was admitted in October 2007 with fever and fatigue for one week. Physical examination showed pallor and severe sternal tenderness. Blood routine showed WBC 93.7×109/L, Hb 80.7g/L, platelets 42×109/L, 60% blast cells. Flow cytometry analysis of marrow mononuclear cells showed 84.41% blast cells positive for CD34, 80.49% for HLA-DR, 34.63% for CD13, and 5.71% for MPO. Karyotype at diagnosis was 46, XX, t (9; 22) (q34; 11) in 10 analyzed metaphases. Major BCR/ABL rearrangement (M-BCR-ABL, P210) was positive tested by real-time quantitative polymerase chain reaction(RQ-PCR). She was diagnosed with Ph+ AML (FAB M0). The patient was treated with 2 courses of DA chemotherapy then achieved bone marrow remission after the first course and achieved Complete Hemotology Response (CHR) after the second course. Then another 2 courses of high dose cytarabine were given. The status of minimal residual disease (MRD) was monitored by RQ-PCR for BCR-ABL/ABL ratio. After that BCR-ABL/ABL ratio was 68%, and then oral treatment with Imatinib 300mg/d×14d was started 4 months after diagnosis. Then 2 more cycles of Imatinib (300 mg/day for 14 days) following IA consolidation chemotherapy were taken and the patient maintained CHR and achieved statuses Complete Molecular Response (CMR) by her BCR-ABL/ABL ratio reducing to 0.4% 8 months after diagnosis. Then she took another course of Imatinib 400mg×4w therapy before allo-SCT. The patient underwent allo-SCT from a HLA-identical unrelated donor 9 months after diagnosis. STR analysis showed completely donor phenotype 1, 3 and 6 months after SCT. Imatinib (300 mg/day) was continued 74 days after SCT and the patient remains continuous CHR with Complete Cytogenetic Response (CCyR) and CMR till now. Patient 2: A 46-year-old man was admitted in Dec. 2004 with fever, cough and fatigue. Physical examination showed pallor and a small submaxillary lymphnode on the right. Blood Routine showed Hb 59g/L, platelets 115×109/L, WBC 3.1×109/L, and 24% blast cells. Bone barrow immunophenotype was CD34+, CD13+, CD117+, HLA-DR+ and MPO-. Karyotype analysis showed 46, XY, t (9; 22) (q34; 11) in 10 analyzed metaphases. Major BCR-ABL rearrangement was positive. He was diagnosed as Ph+ AML (FAB M0). The patient received induction chemotherapy as MA/VP plus Imatinib (400 mg/day×4w) and achieved CHR. Imatinib combined chemotherapy continued for another 7 more cycles. Imatinib was taken as 400 mg/day×2 w during the intermission period of chemotherapy. He had a bone marrow relapse with 18% blasts 48 days after the last chemotherapy, although CCyR and CMR were still maintained. Imatinib was added in a dose of 600mg/day and CHR achieved again 1 month later. The patient then took continuous Imatinib (400mg/day) until he received allo-SCT 26months after diagnosis. STR analysis showed completely donor phenotype 1, 3 and 6 months after SCT. Imatinib (400 mg/day) administration was continued and the patient maintained CHR and CMR in the following clinical course. However, he developed interstitial pneumonia 11 months after SCT and died from severe respiratory failure 30 months after SCT with CHR and CMR still maintained at that time. Our cases indicate that Imatinib combined with daunorubicin based chemotherapy followed by allo-SCT and Imatinib maintenance treatment appears to be the best way to treat Ph+ de novo AML, especially when Imatinib is used in an early phase of AML and when a complete molecular response is achieved before allo-SCT. Disclosures:No relevant conflicts of interest to declare.

Anti‐leukemic activity of valproic acid and imatinib mesylate on human Ph+ ALL and CML cells in vitro

The armamentarium of anti-leukemic drugs has increased substantially since anti-leukemic activities were recently found for a variety of non-classical cytostatic drugs, among them the histone deacetylase (HDAC) inhibitor valproic acid (VPA). This study investigated the effect of VPA on proliferation and apoptosis of human Philadelphia chromosome-positive (Ph+) acute lymphatic (ALL) and chronic myeloid leukemia (CML) cells and on colony formation of human chronic-phase CML progenitor cells. Strong anti-proliferative and pro-apoptotic effects of VPA were observed on human ALL and CML cell lines at concentrations achievable in vivo. These effects were most pronounced in ALL cell lines as well as in primary ALL cells. Notably, VPA revealed enhanced activity with imatinib mesylate, nilotinib, the farnesyl transferase inhibitor SCH66336, interferon-alpha and cytosine arabinoside. VPA inhibited the growth of colony-forming cells from 12 Ph+ chronic-phase CML patients but also of those from normal healthy controls in a dose-dependent fashion. HDAC-inhibiting activity of VPA was confirmed on ALL and CML cells. In conclusion, VPA, whether alone or in combination with other non-classical anti-leukemic compounds, exerts significant anti-leukemic effects on human ALL and CML cells.

Single Center Experience with Philadelphia Chromosome-Positive Acute Myeloid Leukemia.

Background: Rare instances of Philadelphia chromosome-positive (Ph+) acute myeloid leukemia (AML) have been reported, constituting <1% of de novo cases. However, differentiating these cases from chronic myeloid leukemia presenting in blast phase (CML-BP) has proven difficult. Several clinical and pathologic criteria have been proposed to distinguish Ph+ AML from CML-BP, including absence of an antecedent hematologic disorder, lack of evidence of a chronic or accelerated phase of CML after induction therapy, infrequent splenomegaly and peripheral eosinophilia or basophilia, and bone marrow characteristics such as lower cellularity, basophilia, and myeloid:erythroid ratio.Methods: We searched the M.D. Anderson Cancer Center leukemia database to identify all pts that had been diagnosed with Ph+ AML by cytogenetic analysis, between 1980 and 2006. Clinical, laboratory, and hematopathologic data were reviewed in order to separate them into the following groups: Ph+ AML, CML-BP, acute biphenotypic leukemia, and indeterminate. The following scoring system was employed: 1 point (splenomegaly), 1 point (peripheral eosinophilia and/or basophilia), 1 point (bone marrow basophilia or additional copy of Ph+ chromosome or trisomy 8 or isochromosome17). Zero points was classified as Ph+ AML, 1 point as indeterminate, and 2–3 points as CML-BP. If there was evidence of an antecedent or post-remission chronic or accelerated phase, these cases were identified as CML-BP.Results: 31 patients (pts) were identified: 7 (23%) acute biphenotypic leukemia, 11 (35%) CML-BP, 9 (29%) Ph+ AML, and 4 (13%) indeterminate. Among the 9 pts with Ph+ AML the median age at diagnosis was 50 years (range, 35–76), initial white blood cell count 50 (range, 4–210), peripheral blast 64% (range, 0–96), and bone marrow blast 78% (range, 34–98). 7/9 (78%) pts had additional cytogenetic abnormalities apart from t(9;22)(q34;q11), most commonly deletion 7 (n=3). A variety of induction chemotherapy regimens were employed, including cytarabine based (n=6), gemtuzumab ozogamicin-based (n=2), anthracycline based (n=1), and with the addition of imatinib (n=1). 5/9 (56%) pts classified as Ph+ AML achieved a CR or CRp, 3 (33%) died during induction, and 1 (11%) was refractory. 3/5 pts that achieved remission relapsed, with a median CR duration of 35 weeks (range, 20–42) and median OS 58 weeks (range, 55–61). Stem cell transplant was employed in 2 pts, one refractory to induction therapy who died 34 weeks later and one transplanted in CR and alive at 56 weeks; this is also the only pt to be treated with imatinib, as part of induction therapy. The median overall survival for pts classified as Ph+ AML was 34 weeks (range, 2–64) and similar to that of pts reclassified as CML-BP, which was 64 weeks (range, 11–271) (p=0.15).Conclusion: Ph+ AML represents a rare entity that may be mistaken for de novo CML-BP. Herein, we propose a system to help with this differentiation. Clinical outcome is poor with conventional chemotherapy and combinations based on tyrosine kinase inhibitor-based therapy should be investigated.

Philadelphia Chromosome–Positive Acute Myeloid Leukemia

We performed a multi-institutional retrospective analysis of the morphologic features, immunophenotype, cytogenetics, and BCR-ABL transcript characterization of cases of Philadelphia chromosome-positive acute myeloid leukemia (Ph+ AML). We compared these cases with cases of documented chronic myelogenous leukemia in myeloid blast crisis (CML-MBC). Patients with Ph+ AML were less likely to have splenomegaly or peripheral basophilia and had lower bone marrow cellularity and myeloid/erythroid ratios than patients with CML-MBC. Additional specific cytogenetic abnormalities that typically occur in CML-MBC were less common in Ph+ AML. Of 7 patients with Ph+ AML treated with imatinib mesylate, 6 showed at least a partial hematologic response, but the responses were of a short duration (median, 2.5 months). The median survival of patients with Ph+ AML was 9 months, similar to that of patients with CML-MBC (7 months). Ph+ AML is a rare aggressive acute leukemia with some features distinct from CML-MBC.