Adult Acute Nonlymphocytic Leukemia in Saudi Arabia: Experience at King Khalid University Hospital in Riyadh

Abstract

Original ArticlesAdult Acute Nonlymphocytic Leukemia in Saudi Arabia: Experience at King Khalid University Hospital in Riyadh Nagi S. El Saghir, MD Dahish S. Ajarim, MD, FRCP(C) Anthony D. Hall, BPharm Kamal E. Higgy, MB, BCh, DMS, PhD(Cantab) Shihab S. Al-Mashhadani, MB, ChB, FRCPA Khalid S. Al Khairy, MB, BS, MRCPath Abdul-Kareem Al-Momen, MD, FRCP(C) Essam Fawzy, and MB, BCh Cheruppolil R. Santhosh-KumarMRCP Nagi S. El Saghir Address reprint requests and correspondence to Dr. El Saghir: Division of Hematology-Oncology, Department of Medicine (38), King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia. From the Division of Hematology-Oncology, Department of Medicine College of Medicine, King Saud University, and King Khalid University Hospital, Riyadh. Search for more papers by this author , Dahish S. Ajarim From the Division of Hematology-Oncology, Department of Medicine College of Medicine, King Saud University, and King Khalid University Hospital, Riyadh. Search for more papers by this author , Anthony D. Hall From Department of Pharmacy College of Medicine, King Saud University, and King Khalid University Hospital, Riyadh. Search for more papers by this author , Kamal E. Higgy From Department of Hematology Unit, Department of Pathology, College of Medicine, King Saud University, and King Khalid University Hospital, Riyadh. Search for more papers by this author , Shihab S. Al-Mashhadani From Department of Hematology Unit, Department of Pathology, College of Medicine, King Saud University, and King Khalid University Hospital, Riyadh. Search for more papers by this author , Khalid S. Al Khairy From Department of Hematology Unit, Department of Pathology, College of Medicine, King Saud University, and King Khalid University Hospital, Riyadh. Search for more papers by this author , Abdul-Kareem Al-Momen From the Division of Hematology-Oncology, Department of Medicine College of Medicine, King Saud University, and King Khalid University Hospital, Riyadh. Search for more papers by this author , Essam Fawzy From the Division of Hematology-Oncology, Department of Medicine College of Medicine, King Saud University, and King Khalid University Hospital, Riyadh. Search for more papers by this author , and Cheruppolil R. Santhosh-Kumar From the Division of Hematology-Oncology, Department of Medicine College of Medicine, King Saud University, and King Khalid University Hospital, Riyadh. Search for more papers by this author Published Online:1 Mar 1989https://doi.org/10.5144/0256-4947.1989.158SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutAbstractTwenty-two adult patients with acute nonlymphocytic leukemia (ANLL) were analyzed. There were 15 males (68%) and 7 females (32%). Their median age was 42 years. Thirty-six percent had acute myelomonocytic leukemia (M4), and 46% had acute monocytic leukemia (M5), according to the French-American-British classification. Of 17 patients who received intensive combination chemotherapy, 47% achieved complete remission. Of the subgroup of 14 new and previously untreated patients, the complete remission rate was 57%. The rest of the patients died of septic complications. We report an increased ratio of M4 and M5 in ANLL in Saudi Arabia and an increased rate of severe septic and fungal complications.IntroductionUsing the French-American-British (FAB) classification,1,2 a variable incidence of FAB types of acute nonlymphocytic leukemia (ANLL) has been reported from different centers around the world.3-7 The most commonly reported type is acute myeloblastic leukemia with maturation (M2) (25% to 63% of cases). Acute myelomonocytic (M4) and acute monocytic (M5) types are less commonly encountered (8% to 37% and 2% to 32%, respectively). Comparative responsiveness of the FAB types of ANLL to chemotherapy has been variable.3-8 In this retrospective analysis, we report our experience with ANLL in a primary and referral care hospital in Riyadh, Saudi Arabia. We review patient characteristics, incidence of various types of ANLL, results of intensive chemotherapy, septic complications, and survival.PATIENTS AND METHODSPatientsTwenty-two adult patients with ANLL seen at King Khalid University Hospital, Riyadh, from September 1984 through July 1987, from a total of 30 adult patients with acute leukemia (of whom eight patients had acute lymphoblastic leukemia), were analyzed. The patients came directly through our emergency room and clinics or were referred from other hospitals in the country; no selection criteria were applied.DiagnosisAll patients had peripheral blood smears, bone marrow aspirates, and bone marrow biopsies on admission. Morphologic characteristics were evaluated on Wright-Giemsa stained slides. Cytochemical stains were done on all bone marrow smears using Sudan black, dual esterase (al-phanaphthol acetate esterase with sodium fluoride inhibition and chloroacetate esterase),9,10 periodic acid-Schiff (PAS), and acid phosphatase. The slides were examined by all clinicians and hematopathologists together at the time of initial presentation of each patient, and consensus diagnoses were reached in all cases.TreatmentEighteen patients were given intensive chemotherapy with a combination of daunorubi-cin, 45 mg/m2 given as intravenous boluses daily for 3 days; cytarabine, 100 mg/m2 doses given every 12 hours as 1-hour infusions or as 24-hour continuous infusions for 7 to 10 days; and thioguanine, 100 mg/m2 doses given orally every 12 hours for 7 to 10 days. Intensive chemotherapy regimens (referred to in the text as DAT combinations) were given according to the attending physicians’ choice. Consolidation treatment, where given, consisted of the same remission-induction drug combination given for one or two cycles. One of these 18 patients signed himself out of the hospital on day 12 of his treatment and was excluded from further analysis.Three elderly patients with severe underlying medical problems were treated with low-dose cytarabine, 10 mg/m2 subcutaneously twice daily for 21 days.One patient refused chemotherapy.Supportive CareFifteen patients had Hickman central venous catheters inserted during the first few days following admission. Twelve doses of prophylactic vancomycin were administered intravenously in patients in whom Hickman catheters were inserted.Surveillance cultures were taken from sputum, urine, stools, ears, nose, throat, mouth, axillae, perianal regions, and vagina on admission and weekly afterwards.Protective reverse isolation and strict handwashing techniques were instituted in all cases when the absolute neutrophil count was below 1.0×109/L.Empiric antibiotic therapy for pyrexia in neutropenic patients was administered when temperature exceeded 38.5°C on one occasion, or 38°C on two consecutive occasions within 24 hours. Antibiotic therapy was optimized according to microbiological culture reports, and empiric amphotericin B was added at the suspicion of fungal infection or persistence of unexplained fever for 7 days.Transfusions of packed red blood cells were given when clinically indicated. Platelet transfusions were given to thrombocytopenic patients prophylactically when platelet counts went below 200 × 109/L or in cases of hemorrhage. Where possible, platelets were collected by platelet pheresis from single donors or HLA-matched family members whenever refractoriness to pooled blood bank plate ets developed.Criteria for ResponseResponse was assessed by bone marrow aspiration and biopsy evaluation on day 14 of treatment and on day 21 or 28 according to the regimen given. A remission bone marrow was defined as normocellular with a blast count of less than 5%. Complete remission was defined when a remission marrow was achieved along with recovery of peripheral blood counts and absence of blasts.Duration of remission was defined as the period from time of remission until relapse, death, or last follow-up. Survival time was defined as the period from first day of chemotherapy until death or last follow-up.RESULTSSex, Age, and Race DistributionAcute nonlymphocytic leukemia constituted 73% (22 of 30 patients) of all adult leukemia seen at our hospital, while acute lymphoblastic leukemia constituted 27%. Among 22 patients with ANLL, 15 (68%) were males and seven (32%) were females (male:female ratio of 2.1:1). Ages ranged from 14 to 74 years with a mean age of 42 years. Thirteen patients (59%) were Saudi Arabs, three patients (13.6%) were from northern Africa (Egypt, Sudan, and Ethiopia), three patients (13.6%) were from the Indian subcontinent (Pakistan, India, and Sri Lanka), and three patients (13.6%) were from the Philippines.Clinical Presentation and Laboratory DataThe main complaints included fever (in 82% of patients), bleeding (in 55%), and weight loss (in 45%). Main physical features are summarized in Table 1. Hepatomegaly and splenomegaly were particularly common. Initial complete blood cell counts are summarized in Table 2. Significantly, 23% of patients had a leukocyte count between 10 and 45 × 109/L. The percentage of blast cells in the peripheral blood ranged from nil (in three patients) to 94% of the total leukocyte count, with a mean of 48%. The percentage of blasts in the bone marrow ranged from 35% to 95% (mean, 75%) of all nucleated cells.Table 1. Physical signs at presentation.Table 1. Physical signs at presentation.Table 2. Leukocyte count, hemoglobin, and platelet count distributions at presentation.Table 2. Leukocyte count, hemoglobin, and platelet count distributions at presentation.Diagnosis and FAB ClassificationAccording to the FAB classification, of the 22 patients, two (9.1%) had acute myeloblastic leukemia with maturation (M2), two (9.1%) had acute promyelocytic leukemia (M3), eight (36.4%) had acute myelomonocytic leukemia (M4), and ten (45.5%) had acute monoblastic leukemia (M5). No patient had acute myeloblastic leukemia without maturation (Ml) or acute erythroblastic leukemia (M6). Table 3 shows a summary of the results of cytochemical stains of all patients.Table 3. Summary of results of cytochemical stains of bone marrow smears and FAB classification.Table 3. Summary of results of cytochemical stains of bone marrow smears and FAB classification.Two patients had a myelodysplastic syndrome. Of the group of patients who received DAT combination chemotherapy, one patient had a refractory anemia with excess blasts in transformation (RAEB-t), and of the group of patients who received low-dose cytarabine treatment, one patient had a refractory anemia with excess blasts (RAEB).Remission InductionOf 17 evaluable patients who received intensive induction DAT chemotherapy, eight patients (47%) achieved complete remission, one patient (6%) achieved complete remission after one course of chemotherapy on day 26 of treatment, and seven patients (41%) achieved remission after two courses of chemotherapy after 36 to 66 days on treatment. The average time required to achieve complete remission was 50 days (range, 26 to 66 days). Of the 17 patients who received DAT combinations, three had a myelodysplastic syndrome and/or previous intensive chemotherapy (one for a presumed diagnosis of acute lymphoblastic leukemia in Sudan and one for ANLL at Riyadh Central Hospital). For the 14 new and untreated patients, the complete remission rate was 57% (eight patients). Two patients had successful bone marrow transplantation performed at the King Faisal Specialist Hospital and Research Centre in Riyadh, after 2 and 16 weeks of first complete remission.Of the patients who received low-dose cytarabine therapy, one patient showed improvement, and evidence in the peripheral blood of differentiation of monoblasts into mature monocytes.Remission DurationSix of eight patients (75%) in complete remission relapsed after a median remission of 26 weeks. Only one of those relapsed patients achieved a second complete remission and received an autologous bone marrow transplant at King Faisal Specialist Hospital and Research Centre; he died at 109 weeks while in remission. Continuous remission was seen in the remaining two patients in complete remission who received bone marrow transplants; at this writing, one of them remains alive, while the other died of intercurrent illness at 45 weeks of complete remission.SurvivalSurvival of patients treated with combination chemotherapy and the subgroup of new and previously untreated patients is shown in Figures 1 and 2. The median survival time of the entire group of 17 patients who received combination chemotherapy was 6 weeks, 42 weeks for responded and 4 weeks for nonresponders. The median survival time of the subgroup of new and previously untreated patients was 25 weeks, 42 weeks for responders and 4 weeks for nonresponders. The wide difference between median survivals results from the early death of nine patients, including three patients who had a myelodysplastic syndrome and prior chemotherapy. Only one of the eight complete responders, a bone marrow transplant recipient, remains alive at 132+ weeks.Figure 1. Survival of patients who received DAT combination chemotherapy.Download FigureFigure 2. Survival of the subgroup of new and previously untreated patients.Download FigureOne elderly patient responding to low-dose cytarabine was lost to follow-up after 12 weeks.Toxicity and DeathsNine patients (53%) of all 17 who received combination chemotherapy died during remission induction. Seven patients died during the initial phase of treatment after an average of 22 days, and two patients died during treatment for refractory disease on days 39 and 42.All deaths were attributed to sepsis and, in one patient, to sepsis with concomitant hemorrhage. The patient with myelodysplastic syndrome in transformation to acute leukemia died from sepsis on day 16, and the two patients with prior chemotherapy died on days 16 and 42 of chemotherapy. The other four patients died with sepsis after an average of 22 days.Two transplanted patients died from veno-occlusive disease and Pneumocystis pneumonia, respectively, at 45 and 109 weeks of continuous first and second remissions.All relapsed patients died from sepsis and refractory disease, except the one patient who achieved a second complete remission and had an autologous bone marrow transplant and died of intercurrent Pneumocystis pneumonia.Of the three patients who received low-dose cytarabine, one patient died of sepsis on day 11 of treatment and one patient died of hepatic failure on day 27.Prolonged neutropenia was observed in all patients. Positive blood cultures were documented in 24 instances in 12 patients during induction chemotherapy. There were 12 gram-negative septicemias, nine gram-positive septicemias, and three fungemias. Thirteen patients had clinical and radiologic pneumonias. Pneumonia progressed to adult respiratory distress syndrome (ARDS) in seven patients. Of those seven patients with ARDS, five had positive blood cultures, and two had postmortem lung biopsies showing candidiasis.DISCUSSIONThe commonest FAB types we encountered were myelomonocytic (M4) and monocytic (M5) leukemias. This has been reported from Saudi Arabia in abstract form by us (M4 and M5)11,12 and by Spence et al (M4).13 We have used the FAB criteria for diagnosis based on Wright-Giemsa morphology supported by cytochemical stains. There were no significant differences when the entire group of 22 patients was considered (M4: 36%, M5: 46%), or the 17 patients treated with intensive DAT combination chemotherapy (M4: 35%, M5: 47%), or the 14 new and previously untreated patients (M4: 28%, M5: 57%). This high percentage of M4 and M5 subtypes of ANLL, although the total number of patients is small, cannot be easily regarded as merely due to chance (18 of 22 patients). It differs significantly from all reported series from Western centers.3-7The response of ANLL to various induction chemotherapy regimens combining cytarabine, daunorubicin, and thioguanine, in the doses and schedules used in our patients, has been reviewed in the literature with the conclusions that no one way is significantly better, nor could be recommended more than the others14-17; this has allowed us to group our patients together. No attempt was made to compare them because of small numbers.Comparative responses in the literature of acute myeloid, myelomonocytic, and monocytic leukemias to chemotherapy have been variable.3-8,18-21 No significant differences in response rates and survival have been observed by some3,18,19; others found that patients with myelomonocytic leukemia had a longer survival than those with pure myeloid leukemia,5,20 while others found that they had a decreased response rate.4 Patients with monocytic leukemia are reported to have a decreased complete remission rate,7 early relapses and failure to achieve a second complete remission,21 and an apparent decreased survival.8 Our results seem to correlate with these latter observations. This may have influenced our complete remission rate and remission duration which are inferior to overall literature results of complete remission rates of 55% to 88%, median remission durations of 31 to 47 weeks, relapses within 1 to 2 years, and 2-year survivals of 20% to 40%.16,17 Our results also reflect the rather high rate of documented septic complications, and especially fungemias.We emphasize the adverse effect on our results of a high rate of documented septic complications, despite the application of standard prophylactic and therapeutic measures. The high rate of fungemias and fungal pneumonias which progressed to ARDS and death in spite of amphotericin B therapy22 is particularly stressed and should probably be given special attention in the management of patients with acute leukemia in Saudi Arabia.Other poor prognostic factors in our patients include high initial leukocyte counts at presentation, along with a high percentage of blasts both in the peripheral blood and bone marrow, which imply advanced disease at presentation. The significance of hepatosplenomegaly as a prognostic indicator remains to be evaluated in our patient population where hepatitis and parasitic disease are endemic.Only two of our complete remission patients received consolidation chemotherapy. The roles of consolidation and maintenance therapy in acute nonlymphocytic leukemia remain controversial,16,23 although recent literature suggests benefits in remission duration and survival.24-26 The impact of intensive consolidation therapy, with its expected complications, on our patients should be best evaluated in a randomized trial.All six complete remission patients who received chemotherapy only relapsed and died, and our only survivor is one bone marrow transplant recipient. Results of bone marrow transplantation from King Faisal Specialist Hospital and Research Centre have been recently abstracted.26In summary, we have reported an increased rate of myelomonocytic (M4) and monocytic (M5) leukemia in Saudi Arabia, as seen in our hospital. We have drawn attention to the need to conduct prospective clinical studies to characterize poor prognostic factors, to improve remission rates through modification and possibly intensification of combination chemotherapy and use of intensive consolidation chemotherapy, to optimize the prevention and treatment of febrile and infectious episodes, and to confirm the beneficial role of early introduction of amphotericin B therapy.ARTICLE REFERENCES:1. Bennett JM, Catovsky D, Daniel MT, et al.. "Proposals for the classification of acute leukemias: French-American-British (FAB) Co-operative Group" . Br J Haematol. 1976; 33(4):451-8. Google Scholar2. Bennett JM, Catovsky D, Daniel MT, et al.. "Proposed revised criteria for the classification of acute myeloid leukemia: a report of the French-American-British Cooperative Group" . Ann Intern Med. 1985; 103(4):620-5. Google Scholar3. Foon KA, Naiem F, Yale C, Gale RP. 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Google Scholar Previous article Next article FiguresReferencesRelatedDetailsCited byEl Saghir N, Al-Hedaithy S, Hawass N, Fawzy E and Hall A (2019) Pulmonary Aspergillosis Due to Aspergillus Terreus Var. Africanus in Acute Leukemia: Report of a Case and Review of the Literature, Annals of Saudi Medicine , 9:5, (497-501), Online publication date: 1-Sep-1989. Volume 9, Issue 2March 1989 Metrics History Accepted8 July 1988Published online1 March 1989 ACKNOWLEDGMENTThe authors thank Professor R.E. Mass, Dr. J. McIver, Dr. S. Wright, Dr. A.M. Kambal, Dr. N. Sulaiman, medical residents, and our nursing staff for their participation and help in patient management, and Dr. A. Lambourne for his assistance in the statistical analysis. They also thank Dr. A. Padmos, Dr. D. Spence, Dr. H. Clink, and Dr. P. Ernst of the bone marrow transplantation team of King Faisal Specialist Hospital and Research Centre, Riyadh, for performing the transplants on the patients mentioned in the text and for providing them with the necessary follow-up information.InformationCopyright © 1989, Annals of Saudi MedicinePDF download