Acute promyelocytic leukemia current treatment algorithms

In 1957, Hillestad et al. defined acute promyelocytic leukemia (APL) for the first time in the literature as a distinct type of acute myeloid leukemia (AML) with a “rapid downhill course” characterized with a severe bleeding tendency. APL, accounting for 10–15% of the newly diagnosed AML cases, results from a balanced translocation, t(15;17) (q22;q12-21), which leads to the fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA) gene. The PML–RARA fusion oncoprotein induces leukemia by blocking normal myeloid differentiation. Before using anthracyclines in APL therapy in 1973, no effective treatment was available. In the mid-1980s, all-trans retinoic acid (ATRA) monotherapy was used with high response rates, but response durations were short. Later, the development of ATRA, chemotherapy, and arsenic trioxide combinations turned APL into a highly curable malignancy. In this review, we summarize the evolution of APL therapy, focusing on key milestones that led to the standard-of-care APL therapy available today and discuss treatment algorithms and management tips to minimize induction mortality.Subject terms: Chemotherapy, Acute myeloid leukaemia     

滤泡型淋巴瘤治疗后继发急性早幼粒细胞白血病1例报告并文献复习

目的：探讨相关性急性早幼粒细胞白血病（t-APL）的临床特点和治疗。方法：报告1例滤泡型淋巴瘤治疗后的（t-APL）,并复习相关文献。结果：1例38岁的滤泡型淋巴瘤患者共接受了20疗程的化疗,包括6疗程的FND（复达拉滨、米托蒽醌、地塞米松）方案。治疗56个月后,患者出现全血细胞减少,骨髓检查诊断为APL,染色体检查为t（15;17）（q22;q12）。在应用全反式维甲酸、亚砷酸和联合化疗治疗后,获完全缓解,但16个月死于淋巴瘤复发。结论：在以复达拉滨为基础的联合化疗方案治疗滤泡型淋巴瘤时,应考虑可能发生t-APL的危险,需密切监测血细胞变化。     

滤泡型淋巴瘤治疗后继发急性早幼粒细胞白血病1例报告并文献复习

目的:探讨相关性急性早幼粒细胞白血病(t-APL)的临床特点和治疗。方法:报告1例滤泡型淋巴瘤治疗后的(t-APL),并复习相关文献。结果:1例38岁的滤泡型淋巴瘤患者共接受了20疗程的化疗,包括6疗程的FND(复达拉滨、米托蒽醌、地塞米松)方案。治疗56个月后,患者出现全血细胞减少,骨髓检查诊断为APL,染色体检查为t(15;17)(q22;q12)。在应用全反式维甲酸、亚砷酸和联合化疗治疗后,获完全缓解,但16个月死于淋巴瘤复发。结论:在以复达拉滨为基础的联合化疗方案治疗滤泡型淋巴瘤时,应考虑可能发生t-APL的危险,需密切监测血细胞变化。     

Acute promyelocytic leukemia

Opinion statement The treatment of acute promyelocytic leukemia (APL) is different from other subtypes of acute myelocytic leukemia (AML). All trans-retinoic acid (ATRA) is an essential component of the standard remission induction for all newly diagnosed APL patients. Remission induction with ATRA and chemotherapy given concurrently appears to be associated with fewer relapses. With further consolidation chemotherapy without high-dose cytosine arabinoside, the disease-free survival rate can reach 70% to 80%, and many of these patients are cured, more so than in any other AML subtype. APL is especially sensitive to anthracyclines, which should be included in the chemotherapy cycles at a higher dose than in other AML subtypes. Maintenance with low-dose chemotherapy (oral daily 6-mercaptopurine with weekly methotrexate) or ATRA further improves the long-term outcome. New approaches are also available for relapsing patients, although the optimal treatment is unknown. Patients who did not receive oral ATRA in first relapse can be treated with this agent, as can first relapsing patients who have been off the drug for more than 1 year. Because of poor remission rates, ATRA should not be used in patients with second or subsequent relapses (whether ATRA was given in the past), in patients with relapses early after ATRA discontinuation, or in patients relapsing while on ATRA therapy. Arsenic trioxide can also be used, especially in patients resistant to ATRA. Because arsenic trioxide is still experimental and not yet widely available, patients who are unlikely to respond to ATRA or who unsuccessfully undergo ATRA reinduction should be treated with chemotherapy. Patients in second or subsequent remission induced with ATRA or chemotherapy should receive consolidation chemotherapy. When arsenic trioxide is used for reinduction, the drug should be continued for several cycles; however, adding consolidation chemotherapy might improve the results. Because it is unknown whether APL in second or subsequent remission is curable with salvage therapy, allogeneic hematopoietic stem cell transplantation is often considered for patients with a human leukocyte antigen (HL-A)-identical sibling and autologous transplantation when a donor does not exist. However, compared with the new treatments, the role of transplantation for relapse is unclear. In first remission, there is no role for transplantation. A new liposomal formulation of intravenous ATRA is being investigated and seems effective in late first relapses, and it may be able to induce and maintain first remissions in selected patients without chemotherapy.     

Acute non-lymphocytic leukemia and acute myeloproliferative syndrome following radiation therapy for non-Hodgkin's lymphoma and chronic lymphocytic leukemia: cytogenetic studies.

Seven cases of acute nonlymphocytic leukemia (ANLL) and one of malignant myeloproliferative syndrome were identified from a pool of 189 cases of non-Hodgkin's lymphoma (NHL) and CLL treated primarily with extensive radiotherapy at the Clinical Center, the National Institutes of Health. Four patients also received chemotherapy, two for only short periods. The median time interval from the diagnosis of the primary malignancy to the development of leukemia was 61 months (range 33 to 98 months) and the median survival after the diagnosis of leukemia was two months (0 to 9 months). All eight patients were cytogenetically abnormal and serial chromosome studies revealed that hypodiploidy was the most commonly observed chromosomal abnormality. Abnormalities of chromosome no. 7 were seen in all five patients analyzed by the chromosome banding technique; four of them had monosomy 7. The next most frequently involved chromosome was no. 5. The complexity, extensive nature, and long duration of the cytogenetic abnormalities prior to the diagnosis of leukemia in these patients may be characteristic of secondary leukemia in radiation-treated lymphoma and the presence of such anomalies may predict leukemic transformation.     

Acute promyelocytic leukemia in childhood

Acute promyelocytic leukemia (APL) is a relatively rare form of acute myelogenous leukemia (AML). In the United States, APL in children constitutes only 5% to 10% of AML. Molecularly, the disease is characterized by a fusion protein, promyelocytic leukemia (PML)-retinoic acid receptor (RAR)-α that results from a balanced reciprocal translocation between the PML gene on chromosome 15 and the RAR-α (RARA) gene on chromosome 17. A major advance in the field of APL treatment has been the use of all-trans-retinoic acid (ATRA). Advances in the treatment of APL have taken this form of AML from a disease with significant morbidity and mortality to one with an excellent outcome. This has resulted largely from the incorporation of ATRA into frontline regimens with chemotherapy. Anthracyclines remain a cornerstone of treatment at this point. Recent trials have shown a role for arsenic trioxide in both newly diagnosed and relapsed APL.     

Acute nonlymphocytic leukemia and acute myeloproliferative syndrome following radiation therapy for non-Hodgkin's lymphoma and chronic lymphocytic leukemia: clinical studies.

Seven cases of acute nonlymphocytic leukemia (ANLL) and one case of a malignant myeloproliferative syndrome have been seen after extensive radiation therapy for non-Hodgkin's lymphoma or chronic lymphocytic leukemia. A myeloproliferative syndrome with abnormalities in granulocytic, erythrocytic, and thrombocytic cell lines was present in all patients and in seven patients preceded ANLL by 2--18 months. The median time to the development of ANLL after primary disease therapy was 61 months (33--98 range). The leukemia was extremely refractory to therapy and median survival after diagnosis of ANLL was two months (range 0--9 months). Leukemia was seen only in those patients who received multiple courses and multiple techniques of radiation therapy.     

Second cancers following non-Hodgkin's lymphoma

The risk of second malignancies following non-Hodgkin's lymphoma (NHL) was estimated in 29,153 patients diagnosed with NHL between 1973 and 1987 in one of nine areas participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Compared with the general population, NHL patients were at a significantly increased risk of developing second cancers (observed/expected [O/E] = 1.18; O = 1231). The O/E ratio increased significantly with time to reach 1.77 in 10-year survivors. Significant excesses were noted for acute nonlymphocytic leukemia (O/E = 2.88), cancers of the bladder (O/E = 1.30), kidney (O/E = 1.47), and lung (O/E = 1.57), malignant melanoma (O/E = 2.44), and Hodgkin's disease (O/E = 4.16). Chemotherapy appeared related to subsequent acute nonlymphocytic leukemia (ANLL) and bladder cancer. Radiation therapy was associated with ANLL and possibly cancers of the lung, bladder, and bone. Malignant melanoma was not clearly related to initial NHL treatment.     

Risk of non-Hodgkin's lymphoma following tuberculosis

To study the association between chronic infections and non-Hodgkin's lymphoma (NHL), we assessed the risk of NHL in a Swedish cohort of 5050 individuals with tuberculosis 1939-1960. The overall relative risk was moderately increased, largely accounted for by high risks following severe tuberculosis diagnosed a long time ago.     

Acute leukemia following treatment of malignant glioma

We report two patients with acute myeloid leukemia (AML) following therapy for malignant glioma; one was a young women treated heavily with alkylating agents for glioblastoma and the other a young man treated with high doses of procarbazine, lomustine, and vincristine (PCV) for anaplastic astrocytoma. We found 26 other examples of therapy related leukemia in adult and pediatric brain tumor patients. Including our two, there were 12 patients with malignant glioma; median interval from treatment to diagnosis of AML was 31 months. Nine adult malignant glioma patients all received nitrosoureas, some as the sole form of chemotherapy. No definite cases occurred after radiotherapy alone.Based upon analogy with other cancers, the cumulative dose of chemotherapy, especially alkylating agents, is the major risk factor for development of secondary AML. Agents implicated include carmustine (BCNU), lomustine (CCNU), and procarbazine. Conventional radiotherapy appears not to confer additional risk. Progressive macrocytosis, early dose reductions for thrombocytopenia, and refractory anemia may provide early diagnostic clues. Current glioma therapy is leukemogenic but the number of patients who survive the interval required to induce AML is small; nevertheless, the identification of chemosensitive types of glioma, and subgroups of patients who derive the most benefit from chemotherapy, may result in increasing numbers of patients at risk of long term complications. If regimens such as PCV continue to prove valuable in neuro-oncology the risk of leukemia will require integration into the clinical decision process. A search for more effective therapy with minimal mutagenicity remains critical.     

Hodgkin's disease following non-Hodgkin's lymphoma.

The risk of Hodgkin's disease following non-Hodgkin's lymphoma (NHL) was estimated using information collected by the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Histopathologic material representing both diagnoses was reviewed for 11 patients in whom Hodgkin's disease was reported after NHL. Diagnoses of both diseases were confirmed in nine patients. Comparisons with population rates indicated that patients with NHL are at an almost threefold risk of subsequently having Hodgkin's disease. Survival in this series was poor; seven of the nine patients died within 16 months after the diagnosis of Hodgkin's disease.     

Increased risk of lung cancer, non-Hodgkin's lymphoma, and leukemia following Hodgkin's disease

The risk of second cancers (SCs) was assessed in 744 patients with Hodgkin's disease (HD) admitted to The Netherlands Cancer Institute from 1966 to 1983. Sixty-nine SCs were observed one month or more after start of first treatment. These included 14 cases of lung cancer, nine cases of non-Hodgkin's lymphoma (NHL), 16 cases of leukemia, and six cases of the myelodysplastic syndrome (MDS). The median interval between the diagnosis of HD and that of second lung cancer, NHL, and leukemia was 8.1, 13.3, and 5.7 years, respectively. The overall relative risks (RR) (observed/expected [O/E] ratios) of developing lung cancer, NHL, and leukemia were 4.9 (95% confidence limit [CL], 2.7 to 8.2), 31.0 (95% CL, 14.2 to 58.9) and 45.7 (95% CL, 26.1 to 74.2), respectively. At 15 years the cumulative risk of developing an SC amounted to 20.6% +/- 2.9%. The 15-year estimates of lung cancer, NHL, and leukemia were 6.2% +/- 1.9%, 5.9% +/- 2.1% and 6.3% +/- 1.7%, respectively. Increased lung cancer risk following HD has not frequently been clearly demonstrated before; that we were able to demonstrate such risk may be due to the completeness of follow-up over long periods that could be achieved in this study. Excess lung cancer risk was only noted in treatment regimens with radiotherapy (RT); also, all lung cancers arose in irradiation fields. Excess risk of leukemia was only found in treatment regimens involving chemotherapy (CT). For NHL, combined modality treatment was shown to be the most important risk factor. Risk of lung cancer and NHL increased with time since diagnosis. A time-dependent covariate analysis (Cox model) performed on leukemia and MDS showed an increasing risk with intensity of CT, age (greater than 40 years), and a splenectomy.     

Acute promyelocytic leukemia. A childhood cluster

Nine children with acute promyelocytic leukemia (APL) are presented. This series of children represents 7% of all acute leukemias and 21% of acute myelogenous leukemias seen during the same period at the Red Cross War Memorial Children's Hospital. These figures are much higher than the incidence quoted in other series of childhood leukemia. In addition, most of those children came from a confined geographic area. Two of the patients were younger than 2 years of age. The youngest patient with APL previously reported in the literature was 24 months.     

Drug monitoring of PEG-asparaginase treatment in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma

This is an updated review of the pharmacokinetic profile of PEG-asparaginase (PEG-ASNase) in childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL). In a total of 271 children undergoing ALL/NHL or relapsed ALL treatment according to the Berlin-Frankfurt-Münster (BFM) protocols, drug monitoring of ASNase serum activity was performed after PEG-ASNase infusions. From December 1996 to July 2000, 1667 samples after 362 intravenous administrations of either 500, 750, 1000 or 2500 IU/m2 PEG-ASNase were analyzed. Three weeks after infusion when relating the ASNase activity to the four-dose levels significant differences were not observed. Large interpatient variability was seen at each dose level resulting in a relevant number of patients not achieving adequate treatment intensity. Neither the extent of ASNase pre-treatment nor a prior event of a hypersensitivity reaction against unmodified ASNase had any impact on PEG-ASNase pharmacokinetics. It is concluded that escalation of the dose of PEG-ASNase did not result in a significant prolongation of time with activity values considered therapeutic. Depending on the desired endpoint, a second administration of PEG-ASNase seems to be more favorable than increasing the dose. For a safer recommendation, further investigations assessing the pharmacodynamic profile are required. Drug monitoring is advisable for early detection of patients with rapid elimination in order to ensure maximum treatment intensity.     

Current treatment of follicular non-Hodgkin's lymphoma

56200 new cases of NHL are expected to be diagnosed in the United States (US) per year. For reasons that are not fully understood, the number of new cases per year has nearly doubled in the past three decades. Most patients with follicular lymphoma are over 50 years of age and present with widespread disease at diagnosis. Nodal involvement is very common, often accompanied by splenic and bone marrow disease. Despite the advanced stage, the median survival ranges from 8 to 12 years. The vast majority of patients with advanced stage follicular lymphoma are not cured using the current therapeutic options. The rate of relapse is fairly consistent over time, even in patients who have achieved complete responses (CRs) to treatment. Therapeutic options in follicular NHL include watchful waiting, oral alkylating agents, purine nucleoside analogues, combination chemotherapy, interferon and monoclonal antibodies. Radiolabelled monoclonal antibodies, autologous or allogeneic bone marrow or peripheral stem cell transplantation are under current clinical evaluation. The approval of rituximab, an unconjugated chimeric antibody against the CD20 antigen for the treatment of relapsed follicular B-cell NHL marked a milestone in the development of antibody treatment. In addition, newer approaches like radioimmunoconjugates with myeloablative activity induced response rates of 80-100% in heavily pretreated patients. Various clinical trials combining monoclonal antibodies with conventional therapies are currently ongoing to determine whether these new biological agents will alter the natural history of follicular lymphoma.     

The treatment of non-Hodgkin's lymphoma.

Much of the approach to evaluation and management of the non-Hodgkin's lymphomas has been modeled after Hodgkin's disease. However, as the name implies, they are quite different. The non-Hodgkin's lymphomas are a group of diseases and syndromes. These many different presentations, syndromes, and possibly different diseases must be distinguished and separated in order to evaluate results. Advances in pathologic classification attempting to relate the disease to physiological activities of lymphocytes are being made, but a simple, clinically relevant scheme is not available at present. We recognize large differences in nodular vs. diffuse histologic patterns. Non-Hodgkin's lymphoma is only infrequently restricted to a single anatomical area, but when it is, radiation therapy can result in a significant proportion of cures. More widespread disease requires systemic therapy. Most encouraging results are found with whole-body radiation used as a systemic agent with the use of multidrug combination chemotherapy. Perhaps whole-body radiation will be most useful when combined with combination chemotherapy as systemic therapy for some groups of non-Hodgkin's lymphoma.