The Prognostic Significance of c-KIT Mutations in Core Binding Factor Acute Myeloid Leukemia

BackgroundMany recurrent mutations are encountered in core binding factor acute myeloid leukemia (CBF-AML) which may affect the prognosis. Approximately 20 to 45% of CBF-AML patients have KIT mutations which are having poor prognosis and high incidence of relapse. There is still insufficient data to categorize the patients with c-kit mutation into which risk group and there is a debate around whether Tyrosine kinase inhibitors can decrease the relapse risk and improve the prognosis of those patients.Patients and MethodsThis study was conducted throughout a period of 3 years, where 102 CBF-AML were enrolled in our study. We analyzed the incidence of c-KIT exon 8 and 17 D816V mutations in CBF-AML patients and studied the prognosis.ResultsThe prevalence of CBF-AML was 102 of 989 (10.3%), 13.7% and 8.7% in pediatrics and adults’ groups respectively. c-KIT fragment mutation analysis revealed a mutant form in 27 of 102 (26.5%) patients. Exon 8 mutation was found in 4 of 40 pediatric and 2 of 62 adult patients, while exon 17 mutation was found in 9 of 40 pediatric and 12 of 62 adult patients. The c-KIT mutations was more common in t(8;21). There was no significant relationship between c-kit mutation and CR rates, while there was a significant inferior overall, disease free as well as progression free survival in the c-KIT mutant patients as compared to the wild group (P value .045, .036 and .024 respectively) in the pediatric group, however, this significance was not evident in the adults’ group.ConclusionAccording to our study, the results may suggest c-KIT mutation as a poor risk factor in pediatric CBF-AML.     

Outcome of Core Binding Factor Acute Myeloid Leukemia by Receptor Tyrosine Kinase Mutation

BackgroundCore binding factor acute myeloid leukemia (CBF-AML) encodes 2 recurrent cytogenetic abnormalities, t(8;21) and inv(16), which carries an overall good prognosis. However, some patients will develop a relapse. We sought define the unfavorable group of CBF-AML by analysis of (c-KIT and FLT3-ITD) and to correlate them with treatment outcome.Patients and MethodsWe performed a prospective study of 70 patients with CBF-AML diagnosed and managed at the medical oncology department of the (National Cancer Institute), Cairo University, with analysis of c-KIT and FLT3 mutations. All patients had received “3 + 7” induction, followed by 3 to 4 courses of high-dose cytarabine consolidation. The institutional review board approved the present study.ResultsThe median patient age was 31 years (range, 18-60 years), with a male/female ratio of 4:3. Of the 70 patients, 42 (60%) had t(8;21) and 28 had inv(16) (40%). c-KIT mutations (exons 8 and 17) were detected in 10 of 52 tested patients, and FLT3-ITD was detected in 3 of 70 patients. Patients with inv(16) experienced more lymphadenopathy and splenomegaly, had a higher median initial leukocyte count. Hepatitis C antibody positivity (8 of 42) was exclusively present in patients with t(8;21). The median overall survival (OS) was 19.5 months, and the median disease-free survival (DFS) was not reached. Patients with inv(16) had near-significant (P = .07) better DFS than patients with t(8;21). c-KIT mutations had no significant effect on OS or DFS. However, reverse tyrosine kinase mutations had a negative effect on DFS but not OS (P = .04).ConclusionCBF-AML with reverse tyrosine kinase mutation conveys a worse prognosis. Hepatitis C virus antibody positivity might be associated with t(8;21) AML and inv(16) with more extramedullary disease.     

Prognostic of Core Binding Factor (CBF) Acute Myeloid Leukemia With Complex Karyotype

BackgroundCore-binding factor acute myeloid leukemia (CBF AML) with recurrent genetic abnormalities inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/ CBFB-MYH11 are usually prognostically favorable but heterogeneous group and additional abnormalities change their prognosis.Materials and MethodsTo evaluate the impact of a complex karyotype on CBF AML prognosis, we included 24 patients with a median age of 56.4 years (23.2-83.3) and a median number of abnormalities of 5 (4-13).ResultsMedian follow-up was 110.4 months. Among patients with a primary clone, complete remission (CR) was reached in 66.7% of patients. 31.3% of patients experienced AML relapse with a median of 8.5 months. Median OS for transplanted patients was 80.7 versus 40.5 months for non-transplanted patients, excluding the 4 patients with early death. Among patients harboring AML with clonal evolution, CR was reached in 62.5% of patients. 50% of patients underwent allogeneic stem cell transplantation (ASCT). In these, median RFS was 19.3 versus 0 months in non-transplanted patients. Median OS seemed also longer in transplanted patients with 23.5 versus 2.95 months in non-transplanted.ConclusionUse of new treatment and tailored strategy based on measurable residual disease monitoring may now improve these results. However, these data allow us to reconsider the good prognosis historically associated with CBF patients despite of karyotype and the place of ASCT in the strategy.     

Outcomes of Patients With Relapsed Core Binding Factor-Positive Acute Myeloid Leukemia

Purpose

To determine the factors associated with outcomes in patients with core binding factor acute myeloid leukemia (CBF-AML) in first relapse.

Upfront Therapy of Acute Myeloid Leukemia

Acute myeloid leukemia is a clinically and biologically heterogeneous disease. Standard induction chemotherapy, consisting of cytarabine and an anthracycline, has not changed substantially over several decades, and outcomes remain suboptimal, particularly in older patients. Many genetic and molecular changes have been identified that guide selection of post-remission therapy and for which targeted therapies are beginning to be developed and tested. These research efforts are resulting in gradual improvement in outcomes. We will review here recent advances in induction chemotherapy, including anthracycline dose intensification in younger patients, treatment selection and use of novel agents in upfront therapy for older patients, and risk-adapted post-remission therapy.     

Definition of Unfit for Standard Acute Myeloid Leukemia Therapy

Determining who is fit or unfit for standard treatments among older adults with acute myeloid leukemia (AML) remains a challenge. However, available evidence can provide guidance on strategies to assess and categorize fitness. Evidence is strongest to guide identification of “frail” older adults at the time of diagnosis based on performance status, physical function, and comorbidity. Many older adults, with adequate performance status and comorbidity burden, however, may be better characterized as “vulnerable”. These patients have subclinical impairments that limit resilience when stressed with intensive therapies. More sensitive assessment strategies are needed to differentiate fit and vulnerable older adults regardless of chronologic age. Research is ongoing to identify tools and approaches, such as geriatric assessment, that can enhance characterization of fitness for AML therapies. This review will highlight available evidence for assessment of fitness among older adults with AML and discuss implications for practice and research.     

Peripheral Blasts on Day 21 of Induction Chemotherapy in a Patient With Core Binding Factor Acute Myeloid Leukemia: More Than Meets the Eye

The combination of fludarabine, high-dose cytarabine, gemtuzumab ozogamicin, and granulocyte colony-stimulating factor (G-CSF), the FLAG-GO protocol, has resulted in excellent response rates and superior relapse-free survival as first-line therapy for patients with core binding factor acute myeloid leukemia (AML). A side effect of administration of G-CSF is an increase in peripheral white blood cell count and blast cell percentage during the recovery phase of the bone marrow after induction chemotherapy. A 60-year-old man with inversion 16 AML was admitted for induction chemotherapy with the FLAG-GO protocol at our institution. On day 21 of his induction regimen, he was noted to have blasts in both the peripheral smear and in the bone marrow that resolved on their own without any intervention by day 28. Our case report underscores the importance of recognizing this phenomenon associated with the administration of G-CSF, and waiting for 5-7 days before administering re-induction therapy or classifying the disease as primary refractory AML.     

Clinical Outcomes of Patients With Chronic Myeloid Leukemia With Concurrent Core Binding Factor Rearrangement and Philadelphia Chromosome

BackgroundAcquisition of additional cytogenetic abnormalities (ACAs) in addition to Philadelphia chromosome is frequently observed in patients with chronic myeloid leukemia (CML) in advanced phase. The presence of core binding factor (CBF) translocations determines the diagnosis of acute myeloid leukemia regardless of blast percentage, and CBF rearrangements are rarely identified as ACAs.Patients and MethodsA retrospective chart review of patients with CML who had CBF rearrangement, t(8;21) or inv(16), in Philadelphia chromosome-positive clones was conducted. Additional cases of CML with CBF rearrangements were identified through literature review.ResultsBetween August 1997 and December 2014, we identified 11 patients who had Philadelphia chromosome and CBF rearrangement in the same clones: 1 (9%) with t(8;21) and 10 (91%) with inv(16). Nine (82%) patients were in blast phase, and 2 (18%) in second chronic phase. Four (36%) patients received tyrosine kinase inhibitor monotherapy, 2 (18%) received tyrosine kinase inhibitor and chemotherapy, and 5 (45%) received chemotherapy only. Three (27%) patients achieved complete remission with incomplete count recovery, and 4 (36%) had no response after the initial therapy. Three (27%) patients underwent allogeneic stem cell transplantation. The median event-free survival and overall survival for the 11 patients were 2 months and 6 months, respectively. Literature review identified 14 patients with CML with CBF rearrangement with a median overall survival of 14 months.ConclusionAcquisition of CBF rearrangement in addition to Philadelphia chromosome is a rare phenomenon associated with poor prognosis. CBF rearrangements as ACAs in patients with CML can be considered high-risk features.     

Long-Term Results of CAP Therapy in Chronic Lymphocytic Leukemia

This study was designed to study the efficacy and toxicity of an adriamycin-containing regimen (CAP: cyclophosphamide, adriamycin, and prednisone) in patients with previously untreated chronic lymphocytic leukemia (CLL). CAP was given to clinical complete remission followed by 18 months of cyclophosphamide-prednisone (CP) maintenance. Forty-seven patients with previously untreated CLL were treated. These patients initially presented with advanced stage (Rai III or IV) or had less advanced stage (Rai 0-II) patients and demonstrated evidence of disease progression. Patients received 750 mg/m² of cyclophosphamide intravenously on day 1, 50 mg/m² of adriamycin intravenously on day 1 and 100 mg/day of prednisone on days 1-5. Courses were repeated at 3-week intervals until clinical CR, at which time maintenance with cyclophosphamide and prednisone (CP) was commenced. A maximum cumulative dose of 450 mg/m² of adriamycin (9 courses of CAP) was given. Twenty (43%) of 47 patients obtained a CR and 11 (23%) obtained a partial remission. Bone marrow biopsy criteria were used to define response in addition to clinical and peripheral blood responses. All patients have been followed for 10 years. The median survival was 259 weeks. No patient remains in remission. No impact of response on survival was found. Surprisingly, the response rate and survival were higher and longer for patients with more advanced stages and higher tumor burdens. The median survival times for patients with Rai stage IV and Binet stage C disease were 93 months and 81 months, respectively. Although the regimen was well tolerated, three patients, each with an antecedent cardiac risk factor, developed congestive heart failure. Adriamycin containing regimens can be safely given to elderly patients with CLL and show promise in the treatment of advanced stage disease.     

The Binding of Acute Myeloid Leukemia Blast Cells to Human Endothelium

AML blast cell adhesion to endothelium is in all likelihood a prerequisite for blast cell migration across the vascular wall in the periphery and the subsequent establishment of leukemic extravascular disease. A general feature of malignant cells is their acquisition of altered or aberrant adhesive capabilities which appear to be associated with their ability to metastasize. Aberrant expression of integrin adhesion molecules and of membrane oligosaccharide structures is found in AML and various solid tumors. With respect to AML, these alterations in adhesive phenotype may confer a proliferative advantage on the malignant cells in the marrow, may facilitate egress from the bone marrow into the peripheral vasculature and may enable AML blast cells to traverse the vessel wall and so establish extravascular disease. Oncogenes may be directly involved in the acquisition of such aberrant adhesive phenotypes. Neutrophil extravasation is described as a model for leukocyte migration across the vessel wall and brief summaries of experimental work involving aspects of AML blast cell and normal CD34+ bone marrow cell adhesion to endothelium in vitro are described.     

Quality of Life and Long-Term Therapy in Patients with Chronic Myeloid Leukemia

Since the development of imatinib and other tyrosine kinase inhibitors (TKIs), the prognosis for patients with chronic myeloid leukemia (CML) has markedly improved, such that most patients diagnosed with CML can now expect to live with their disease rather than die from it. However, most patients will require long-term treatment, which has deleterious effects on health-related quality of life. We review recent literature on drug-related adverse effects, long-term medication adherence, limitations to fertility and pregnancy, effects on cognitive function, ability to work, financial toxicity, pediatric populations, and treatment discontinuation. While patients with CML are fortunate to have excellent therapies available to control their disease, many are unable to lead normal lives, which challenges the notion that research is no longer needed in CML. Curing CML, i.e., no detectable disease and no need for daily medications, should remain the ultimate goal.     

Treatment Strategies in Patients with Core-Binding Factor Acute Myeloid Leukemia

Core-binding factor acute myeloid leukemias (CBF AML) are characterized by sensitivity to high-dose cytarabine. Due to good prognosis in CBF AML patients, it is important to determine the optimal treatment. Long-term RFS (relapse-free survival) is reported among 40–60%. Experience with FA/FLAG vs. IA/IAG as front-line chemotherapy has been reported by some authors. Other studies, regarding treatment strategies such as high-dose daunorubicin, do not determine survival curves in this precise subgroup of patients. Preliminary data with gemtuzumab ozogamicin plus FLAG has been reported. There are not studies with FLAG using oral fludarabine in acute leukemia patients.     

Acute Myeloid Leukemia Possibly Producing Thrombopoietic Factor(s)

A 75-year-old man developed a cluster of differentiation (CD)4-positivebut human T-cell lymphotropic virus type I (HTLV-I)-negativeT lymphoid neoplasm with overwhelming cutaneous involvementand mild thrombocytosis. Twelve courses tetrahydropyranyl adriamycin,cyclophosphamide, vincristine and predonisone (THP-COP) combinationchemotherapy led him to complete remission. After four monthsof complete remission, however, atypical immature cells (blasts)appeared in peripheral blood and bone marrow. Surface markeranalysis revealed the blasts to be CD2–, CD3–, CD4–,CD5–, CD7+, CD8–, CD10, CD13±, CD19–,CD20–, CD25–, CD33+ and human leukocyte antigen-DR(HLA-DR+). Staining for myeloperoxidase, esterases, PAS andplatelet peroxidase were all negative. The patient was diagnosedas having both CD7 and CD33 positive acute myeloid leukemia(AML). The relation between the T cell lymphoid neoplasm andAML was not clear. Thrombocytosis became more marked after acuteleukemia occurred and the platelet count varied in parallelwith the blast cell count in peripheral blood. When the leukemiccell count was high, thrombopoietic activity could be detectedin the serum. In addition, conditioned medium obtained fromprimarily-cultured blasts had detectable thrombopoietic activity,which implied the blasts directly to produce a thrombopoieticfactor(s). Analysis of the serum concentration for cytokineswith associated thrombopoietic activity indicated that the blastspossibly produced a thrombopoietic factor(s) distinct from interleukin(IL)6, IL3, leukemia inhibitory factor (LIF), erythropoietinand granulocyte macrophagecolony stimulating factor. To ourknowledge, this is the first reported case of an acute myeloidleukemia with marked thrombopoiesis (more than 2000x10³/µlof maximum platelet count in peripheral blood).     

Antibody Therapy in Acute Myeloid Leukemia: Current Status and Future Directions

Monoclonal antibodies have become an important modality for cancer therapy. The genetically engineered, humanized anti-CD33 antibody HuM195 has demonstrated modest activity against overt relapsed acute myeloid leukemia (AML) and more substantial activity against minimal residual disease in acute promyelocytic leukemia. Radioimmunotherapy with β-particle–emitting isotopes has eliminated large leukemic burdens while minimizing radiation exposure to normal tissues in both nonmyeloablative and myeloablative regimens. Targeted β-particle immunotherapy with agents such as bismuth 213–labeled HuM195 offers the possibility of a more selective tumor cell kill with less damage to surrounding normal cells. Directed chemotherapy using the anti-CD33–calicheamicin conjugate gemtuzumab ozogamicin (Mylotarg®) has produced remissions in patients with relapsed AML.     

Acute Myeloid Leukemia in the Elderly: A Critical Review of Therapeutic Approaches and Appraisal of Results of Therapy

In the elderly, acute myeloid leukemia (AML) is characterized by a poorer prognosis than in younger patients, due to either host related factors (poor performance status, co-morbid diseases, organ function impairment) or the biology of leukemia itself (high incidence of adverse cytogenetic abnormalities, high frequency of preceding myelodysplastic syndromes, intrinsic resistance to cytotoxic drugs). Current therapeutic results are mostly unsatisfactory and studies reporting high rates of complete remission are probably influenced by selection biases as suggested by the low rate of elderly patients inclusion into cooperative trials. Availability of intensive support including hematopoietic growth factors could stimulate clinicians to manage an increasing number of elderly patients with AML with aggressive programs. However, chemotherapy in the elderly is difficult, costly and usually associated with high morbidity and mortality rate. Therefore, all efforts should be made to identify those subset of elderly patients in whom aggressive treatment may result in a true improvement of disease free and overall survival. The critical analysis of our five years experience, as reported here, seems to suggest that older AML patients displaying unfavourable prognostic factors at diagnosis (i.e., adverse karyotype and high serum LDH levels), but clinically eligible for intensive chemotherapy, do not actually benefit from an aggressive approach. A blind attempt to treat these patients aggressively may be associated with a life threatening toxicity not counterbalanced by an actual survival advantage. We suggest therefore that aggressive treatment should be reserved for elderly AML cases in whom the presence of good prognostic factors at diagnosis predicts that the loss of some patients due to toxicity may be balanced by the achievement of a substantial proportion of long term survivors. Finally, given the biological and clinical heterogeneity of elderly AML patients, a more precise prognostic categorization of these patients would be particularly useful in interpreting future therapeutic results.     

Immunotherapy of Acute Myeloid Leukemia: Current Approaches

Following standard therapy that consists of chemotherapy with or without stem cell transplantation, both relapsed and refractory disease shorten the survival of acute myeloid leukemia (AML) patients. Therefore, additional treatment options are urgently needed, especially to fight residual AML cells. The identification of leukemia‐associated antigens and the observation that administration of allogeneic T cells can mediate a graft‐versus‐leukemia effect paved the way to the development of active and passive immunotherapy strategies, respectively. The aim of these strategies is the eradication of AML cells by the immune system. In this review, an overview is provided of both active and passive immunotherapy strategies that are under investigation or in use for the treatment of AML. For each strategy, a critical view on the state of the art is given and future perspectives are discussed.     

Long-Term Outcome of Postremission Chemotherapy for Adults with Acute Myeloid Leukemia Using Different Dose-Intensities

The long-term results of postremission chemotherapy for 122 consecutive, unselected adults (15-65 years) with acute myeloid leukemia (AML) were assessed in two sequential prospective studies involving an identical 3/7-type induction regimen, and in those achieving remission, another course for early consolidation using 1 day of daunorubicin instead of three. Forty-one patients reaching C.R. during the first study period, were treated with an intensive ablative maintenance (“IM”) program for a period of 9 months. They were randomized to either 6 cycles of induction-type regimen or to 6 cycles of an alternating-type regimen consisting of high-dose (HD)-Ara C/AMSA or 5-azacytidine/AMSA every 6 weeks. There was no difference in disease-free survival (DFS) or survival. Results are compared with 27 patients reaching C.R. on the subsequent protocol where IM was replaced by intensive, short-term consolidation (“IC”) using 1 cycle of intermediate-dose Ara C plus AMSA and 1 cycle of HD-AraC/AMSA. Fifteen patients received both courses of IC as scheduled, 12 refused the second cycle. There was no significant difference in DFS or survival. Seventeen out of the 122 patients refused either IM or IC following early consolidation (“refusals”). They received no further treatment and served as control. Fourteen percent of all patients underwent autologous or allogeneic bone marrow transplantation (BMT) at different stages of their disease, equally distributed amongst the IM and IC-group. Median DFS was 3.3 months in the refusal group, 12.4 months in the IM-group, and 18.4 months in the IC-group when censored for BMT (p = 0.01) with 6%, 12%, and 40% in C.C.R. at 50 months. Accordingly, median survival was 5.4, 20 and 47 months (p = 0.001) with 6%, 15%, and 45% of patients alive at 5 years. There was a definite trend (p = 0.14) for a higher proportion of long-term survivors in the IM-group when BMT was performed (not censored), while long-term survival was identical in the IC-group whether BMT was considered for analyses (not censored) or not (censored). Median follow-up for both studies is 5.6 years, the longest, 10 years. In conclusion, progressive increments in the intensity of postremission therapy yields in a graded, significant improvement of remission duration and survival.     

Antibody-Based Treatment of Acute Myeloid Leukemia

While antibody-based therapies have emerged as clinically effective approaches for several hematologic and solid malignancies, they have not played a significant role to date in the treatment of acute myeloid leukemia (AML). More recently, improvements in antibody-drug conjugate technology, bispecific antibodies, as well as identification of novel AML antigens have re-invigorated enthusiasm for antibody-based therapies for AML. This review describes experiences with former and existing antibody-based therapies for AML, including unconjugated antibodies, antibody-drug conjugates (ADCs), radio-labelled antibodies, and immune-engaging antibodies, and discusses the promise and challenges associated with each.