Jacob M. Rowe

All-trans-Retinoic Acid in Acute Promyelocytic Leukemia

BACKGROUND All-trans-retinoic acid induces complete remission in acute promyelocytic leukemia. However, it is not clear whether induction therapy with all-trans-retinoic acid is superior to chemotherapy alone or whether maintenance treatment with all-trans-retinoic acid improves outcome. METHODS Three hundred forty-six patients with previously untreated acute promyelocytic leukemia were randomly assigned to receive all-trans-retinoic acid or daunorubicin plus cytarabine as induction treatment. Patients who had a complete remission received consolidation therapy consisting of one cycle of treatment identical to the induction chemotherapy, then high-dose cytarabine plus daunorubicin. Patients still in complete remission after two cycles of consolidation therapy were then randomly assigned to maintenance treatment with all-trans-retinoic acid or to observation. RESULTS Of the 174 patients treated with chemotherapy, 120 (69 percent) had a complete remission, as did 124 of the 172 (72 percent) given all-trans-retinoic acid (P=0.56). When both induction and maintenance treatments were taken into account, the estimated rates of disease-free survival at one, two, and three years were 77, 61, and 55 percent, respectively, for patients assigned to chemotherapy then all-trans-retinoic acid; 86, 75, and 75 percent for all-trans-retinoic acid then all-trans-retinoic acid; 75, 60, and 60 percent for all-trans-retinoic acid then observation; and 29, 18, and 18 percent for chemotherapy then observation. By intention-to-treat analysis, the rates of overall survival at one, two, and three years after entry into the study were 75, 57, and 50 percent, respectively, among patients assigned to chemotherapy, and 82, 72, and 67 percent among those assigned to all-trans-retinoic acid (P= 0.003). CONCLUSIONS All-trans-retinoic acid as induction or maintenance treatment improves disease-free and overall survival as compared with chemotherapy alone and should be included in the treatment of acute promyelocytic leukemia.

Chemotherapy Compared with Autologous or Allogeneic Bone Marrow Transplantation in the Management of Acute Myeloid Leukemia in First Remission

BACKGROUND In young adults with acute myeloid leukemia, intensive chemotherapy during the initial remission improves the long-term outcome, but the role of bone marrow transplantation is uncertain. We compared high-dose cytarabine with autologous or allogeneic marrow transplantation during the first remission of acute myeloid leukemia. METHODS Previously untreated adolescents and adults 16 to 55 years of age who had acute myeloid leukemia received standard induction chemotherapy. After complete remission had been achieved, idarubicin (two days) and cytarabine (five days) were administered. Patients with histocompatible siblings were offered allogeneic marrow transplantation, whereas the remaining patients were randomly assigned to receive a single course of high-dose cytarabine or transplantation of autologous marrow treated with perfosfamide (4-hydroperoxycyclophosphamide). Oral busulfan and intravenous cyclophosphamide were used as preparative regimens for both allogeneic and autologous marrow transplantation. The end points were survival from the time of complete remission and disease-free survival. RESULTS In an intention-to-treat analysis, we found no significant differences in disease-free survival among patients receiving high-dose chemotherapy, those undergoing autologous bone marrow transplantation, and those undergoing allogeneic marrow transplantation. The median follow-up was four years. Survival after complete remission was somewhat better after chemotherapy than after autologous marrow transplantation (P=0.05). There was a marginal advantage in terms of overall survival with chemotherapy as compared with allogeneic marrow transplantation (P=0.04). CONCLUSIONS A postinduction course of high-dose cytarabine can provide equivalent disease-free survival and somewhat better overall survival than autologous marrow transplantation in adults with acute myeloid leukemia.

Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710

Arsenic trioxide (As(2)O(3)) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ≥ 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As(2)O(3) consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As(2)O(3) consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As(2)O(3) arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As(2)O(3) arm, 90% compared with 70% at 3 years (P < .0001). The addition of As(2)O(3) consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).

One hundred autotransplants for relapsed or refractory Hodgkin's disease and lymphoma: value of pretransplant disease status for predicting outcome.

PURPOSE One hundred autotransplants for Hodgkins disease (HD) or non-Hodgkins lymphoma (NHL) were examined prospectively to identify variables with prognostic significance. PATIENTS AND METHODS Ninety-six patients with relapsed or refractory HD or NHL underwent 100 autotransplants. Patients received high-dose carmustine (BCNU), etoposide, cytarabine, and cyclophosphamide (BEAC) followed by unpurged autologous stem-cell rescue. RESULTS The 3-year actuarial event-free survival (EFS) rate for the 47 HD patients is 49%, with a median followup duration of 2 years. For the 53 NHL patients, the 3-year actuarial EFS rate is 40%, with a median follow-up duration of 19 months. By multivariate analysis, minimal disease on admission (all areas < or = 2 cm) is associated with improved EFS (HD, P = .003, NHL, P = .03). The projected EFS rate for HD patients entering with minimal disease is 70% versus 15% for patients with bulky disease (P = .0001). The projected EFS rate for NHL patients with minimal disease is 48% versus 25% for patients with bulky disease (P = .04). Posttransplant involved-field radiotherapy, administered to 26 of the last 61 patients, was associated with an improved EFS rate for NHL patients (P = .015). The BEAC regimen was well tolerated by patients who entered the study with minimal disease (mortality rate, < 5%), but caused significant toxicity in patients with bulky disease (mortality rate, 25%). CONCLUSION Disease burden before autotransplantation is an important predictor of regimen-related toxicity and EFS. Posttransplant involved-field radiotherapy may improve outcomes in select patients with NHL. The BEAC regimen is safe and effective, particularly for patients with minimal disease.

Analysis of Factors That Correlate With Mucositis in Recipients of Autologous and Allogeneic Stem-Cell Transplants

PURPOSE To identify predictors of oral mucositis and gastrointestinal toxicity after high-dose therapy. PATIENTS AND METHODS Mucositis and gastrointestinal toxicity were prospectively evaluated in 202 recipients of high-dose therapy and autologous or allogeneic stem-cell rescue. Of 10 outcome variables, three were selected as end points: the peak value for the University of Nebraska Oral Assessment Score (MUCPEAK), the duration of parenteral nutritional support, and the peak daily output of diarrhea. Potential covariates included patient age, sex, diagnosis, treatment protocol, transplantation type, stem-cell source, and rate of neutrophil recovery. The three selected end points were also examined for correlation with blood infections and transplant-related mortality. RESULTS A diagnosis of leukemia, use of total body irradiation, allogeneic transplantation, and delayed neutrophil recovery were associated with increased oral mucositis and longer parenteral nutritional support. No factors were associated with diarrhea. Also, moderate to severe oral mucositis (MUCPEAK > or = 18 on a scale of 8 to 24) was correlated with blood infections and transplant-related mortality: 60% of patients with MUCPEAK > or = 18 had positive blood cultures versus 30% of patients with MUCPEAK less than 18 (P =.001); 24% of patients with MUCPEAK > or = 8 died during the transplantation procedure versus 4% of patients with MUCPEAK less than 18 (P =.001). CONCLUSION Gastrointestinal toxicity is a major cause of transplant-related morbidity and mortality, emphasizing the need for corrective strategies. The peak oral mucositis score and the duration of parenteral nutritional support are useful indices of gastrointestinal toxicity because these end points are correlated with clinically significant events, including blood infections and treatment-related mortality.

Hypocellular myelodysplastic syndromes (MDS): new proposals.

Summary. To determine whether hypocellular MDS differs from normo/hypercellular MDS, we attempted to identify hypocellular MDS cases either by correcting the bone marrow (BM) cellularity by age (28 patients) or by using a single arbitrary value of BM cellularity (25 patients) and compared these two groups of hypocellular cases to the normo/hypercellular MDS cases (72 patients). 18 patients were common to both hypocellular groups. Patients with hypocellular MDS in both of these selected groups have similar features with regard to age and sex distribution, peripheral blood and bone marrow parameters, FAB subtypes, karyotypes, leukaemic transformation, and survival. However, the median age of patients in < 30% BM cellularity group was higher than those patients in the age‐corrected group (69 years v 62 years). The selection of < 30% cellularity excluded 10 cases in the age group < 70 years but included another seven patients in the age group of > 70 years. However, correction of BM cellularity by age revealed that those included patients (selected for < 30% cellularity) who had normocellular BM by their age. Therefore we recommend the age‐correcting grouping to ensure comparable series for comparison, for response to treatment, and survival. Finally, BM cellularity does not appear to be an important factor on prognosis in MDS, because patients with hypocellular MDS in both selected groups have similar prognosis to those with normo/hypercellular MDS patients.

Leukemogenic potential of adjuvant chemotherapy for early-stage breast cancer: the Eastern Cooperative Oncology Group experience.

PURPOSE Since large numbers of patients with early-stage breast cancer now receive adjuvant chemotherapy containing cyclophosphamide, a known leukemogenic agent, it is important to determine the risk of secondary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Therefore, we identified all cases of AML or MDS developing in patients treated on six clinical adjuvant chemotherapy trials conducted by the Eastern Cooperative Oncology Group (ECOG). PATIENTS AND METHODS The patients population included 2,638 patients with previously untreated primary operable breast cancer entered onto six clinical trials conducted by the ECOG between 1978 and 1987. There are 19,200 persons-years of follow-up study and a mean follow-up duration of 7.3 years. Clinical data were obtained from flow sheets submitted to the ECOG Data Management Office. RESULTS Of 2,638 patients at risk with 19,200 person-years of follow-up study, three patients developed MDS (two with a characteristic cytogenetic abnormality). Two patients developed acute leukemia; however, one had adult T-cell leukemia associated with human T-lymphotrophic virus type 1 (HTLV-1) and a second patient developed AML after receiving additional cyclophosphamide for metastatic breast cancer. The estimated incidence rate for MDS is three per 19,200 or 16 per 100,000 person-years of follow-up study with a 95 percent confidence interval of three to 46 per 100,000 person-years. If all five patients (three MDS and two acute leukemia) are included, the estimated incidence rate is five per 19,200 or 26 per 100,000 person-years of follow-up study with a 95 percent confidence interval of eight to 61 per 100,000 person-years. CONCLUSION These data suggest that the risk of secondary AML or MDS among patients with early breast cancer who receive standard-dose cyclophosphamide-containing adjuvant chemotherapy is not much higher than in the general population. However, physicians must remain alert to the possible long-term consequences of alkylating agent and anthracycline-based chemotherapy.

Biologic heterogeneity in Philadelphia chromosome-positive acute leukemia with myeloid morphology: the Eastern Cooperative Oncology Group experience

Evaluable karyotypes were available in 776 of 1148 adult patients who were entered on acute myeloid leukemia (AML) treatment protocols of the Eastern Cooperative Oncology Group. Among these, we found seven patients (0.9%) with t(9;22)(q34;q11), the Philadelphia (Ph) chromosome, in bone marrow metaphases. All fulfilled the FAB criteria for AML (three M0, two M1, two M2), although one patient presented with an additional, distinct lymphoid blast cell population. Chromosomal aberrations in addition to the Ph chromosome were seen in four patients (including two cases of monosomy 7). Molecular analysis by polymerase chain reaction in four patients tested revealed variable BCR/ABL transcript forms (ela2, b2a2, b3a2, b2a3+e1a2). By immunophenotyping, all seven patients were myeloid based on the overall antigen expression pattern. However, all but one demonstrated lymphoid-associated antigens on the myeloid blast cells. The six evaluable patients failed to respond to treatment with a standard anthracycline/cytosine arabinoside-containing regimen. We conclude that the incidence of the Ph chromosome in AML is very low. Although both genotypically and phenotypically heterogenous, Ph chromosome-positive AML, represents a clinically distinct entity with poor outcome.

The role of ABO matching in platelet transfusion

Abstract:  A prospective controlled trial was performed to determine whether the use of ABO‐identical platelets from the start of treatment might provide higher post‐transfusion platelet increments, reduce the number of platelet transfusions and ultimately delay the onset of refractoriness. Forty newly diagnosed patients with haematological diseases were randomized to receive either pooled ABO‐identical platelets or pooled platelets unmatched for ABO group throughout their course. The corrected platelet count increments (CCI) were calculated for the first 25 transfusions of each patient and non‐immune factors present at the time of each platelet transfusion were documented. The mean CCI for the first 25 transfusions in the ABO‐identical group was significantly higher (6600 ±: 7900 SD) than that achieved with ABO unmatched platelets (5200 ±: 7900; p<0.01). The effect was most marked for the first 10 transfusions for each patient where the CCI was 64% higher in the ABO‐identical group (8200 ±: 7500 vs 5000 ±: 8100; p<0.0002). Patients given ABO‐identical platelets required only about half as many transfusions in the first 30 days (10 versus 17, p<0.05) or during the first admission (11 versus 21 p<0.01) as patients in the ABO‐unmatched group. A smaller percentage of patients in the ABO‐identical group became refractory (36% vs 75% p<0.03). The data suggest that patients requiring long‐term platelet support should be transfused with ABO‐identical platelets.

Recommended Guidelines for the Management of Autologous and Allogeneic Bone Marrow Transplantation: A Report from the Eastern Cooperative Oncology Group (ECOG)

Allogeneic bone marrow transplantation has been used for many years to provide definitive therapy for acute and chronic myeloid leukemia, acute lymphoid leukemia, aplastic anemia, and several congenital deficiencies of the bone marrow and immune systems [1-4]. More recently, diseases such as multiple myeloma and the myelodysplastic syndromes, formerly thought to be incurable, are treated successfully using allogeneic bone marrow transplantation [5, 6]. Further advances have led to the use of histocompatible, unrelated bone marrow donors for those patients who do not have a histocompatible sibling donor [7]. The use of autologous bone marrow as the source of the hematopoietic stem cells after administration of high-dose therapy is the most common form of transplantation and now is frequently used to provide curative therapy for acute myeloid leukemia, non-Hodgkin lymphoma, Hodgkin disease, and multiple myeloma [8-12]. In recent years, patients with solid tumors such as breast cancer and germ-cell tumors, even in advanced stage, have attained long-term, disease-free survival using autologous bone marrow transplantation [13-16]. The management of patients having autologous and allogeneic bone marrow transplantation is intricate and involves providing complex care for severely ill and immunocompromised persons. Furthermore, guidelines, procedures, and techniques may vary clinically among transplant centers, sometimes making it difficult to interpret, compare, and collate results among the various institutions. To answer important questions about bone marrow transplantation, oncology cooperative groups have assumed an important role in clinical bone marrow transplantation trials because large patient samples can be accrued in shorter periods. This approach mandates greater uniformity in therapy and supportive care. The Eastern Cooperative Oncology Group (ECOG) has been conducting major trials involving bone marrow transplantation for adult patients, both autologous and allogeneic, since 1984. The need for basic guidelines for acceptance of centers into cooperative group trials is critical both to assure quality and to compare, correlate, and interpret results. Apart from emphasizing the need for a standardized approach in the care of patients receiving bone marrow transplantation, ECOG stresses the latitude and flexibility given to investigators in known as well as unknown areas and strongly encourages participation in established and innovative trials. This approach allows for participation of both very large and small centers. Even though other organizations have formulated guidelines [17-19], we hope that these ECOG guidelines will prove helpful to clinicians who are establishing bone marrow transplantation centers. We assume a certain expertise in the management of neutropenic patients after chemotherapy and, therefore, do not discuss such subjects as the antibacterial management of febrile patients, the prophylaxis and treatment of mucositis, the use and timing of total parenteral nutrition, and the management of central venous catheters in this review. Further, because specifics regarding diseases, conditioning regimens, or marrow purging are protocol specific, we do not address them. Graft-versus-Host Disease The guidelines for allogeneic bone marrow transplantation in this report refer exclusively to sibling six-antigen HLA-A, B, C, D/DR match and do not deal with unrelated donors or partially compatible donors in whom the incidence of failure to engraft and graft-versus-host disease (GVHD) may be higher [20-22]. Although the outcome in five of six antigen family matches may be similar to a six-antigen match [23], mismatches are currently excluded from ECOG allogeneic trials. The grading of GVHD has had practically uniform acceptance since its classic description in the early 1970s [23-25]. The diagnosis and grading of acute and chronic GVHD can be reproduced among bone marrow transplantation centers, at a high concordance rate, as shown by the International Bone Marrow Transplant Registry [26, 27]. For practical reasons, it is reasonable to separate the grading of GVHD into acute GVHD and chronic GVHD and to describe the histologic as well as the clinical staging of each type. Because the signs and symptoms associated with GVHD may be nonspecific, histologic confirmation using skin biopsy, endoscopic biopsy, and liver biopsy whenever possible is strongly recommended. It is essential to determine the incidence and to quantify the extent of GVHD in clinical trials because the morbidity and mortality are a function of extent and severity of both acute and chronic GVHD. Acute Graft-versus-Host Disease Histologic grading (Table 1) was initially described in 1975 [28] and was only sightly modified over the next decade [29-31]. Acute GVHD was usually observed within 30 to 40 days of marrow infusion, but with the advent of more potent immunosuppressive agents such as cyclosporine, its onset may now be delayed by several months [32]. Table 1. Histologic Grading of Acute Graft-versus-Host Disease An overall standardized grading system takes into account the varying clinicopathologic involvement by different organs; although acceptance has been almost uniform, minor differences are present in some centers (Table 2) [29, 33, 34]. Nevertheless, a most recent adaptation seems workable (Table 3) and has been adopted by ECOG [35]. This approach allows assignment of a stage when skin, liver, and gut are affected to different degrees. Table 2. Clinical Staging of Acute Graft-versus-Host Disease* Table 3. Overall Clinical Staging for Acute Graft-versus-Host Disease* Chronic Graft-versus-Host Disease Chronic GVHD usually occurs more than 100 days after allogeneic bone marrow infusion, and the clinical pattern differs somewhat from that seen in acute GVHD (Table 4). Chronic GVHD arises most commonly in patients with active acute GVHD (progressive) but also can be seen in a patient with inactive acute GVHD (quiescent) or in a patient who did not have evidence of acute GVHD (de novo). Most clinical pathologic classifications are based on the extent of the overall disease, and it is this form of functional classification that has been adopted most widely [36, 37]. It is based on the fact that chronic GVHD is a multiorgan disorder in which the severity of individual organ involvement does not correlate well with the overall survival but rather with the patients functional performance [38]. Chronic GVHD is categorized as either limited (localized skin involvement or hepatic dysfunction or both) or extensive; the latter is associated with a worse prognosis. Table 4. Acute Compared with Chronic Graft-versus-Host Disease Prophylaxis of Graft-versus-Host Disease The development of GVHD may confer some antitumor benefit because the normal, immunocompetent donor cytotoxic T lymphocytes may destroy residual host tumor cells [39-42]. The high morbidity and mortality rates of GVHD, however, militate for prophylactic therapy. No standard prophylactic therapy for GVHD exists, but there are two basic approaches to GVHD prophylaxistreatment of the recipient with pharmacologic agents (primarily cyclosporine) and in vitro purging of donor T lymphocytes from the marrow. Since its introduction in the early 1980s, cyclosporine has been the cornerstone of most GVHD prophylaxis protocols. Most centers in the United States use one of two approaches, which begin immediately after marrow infusioneither a combination of cyclosporine plus a short course of methotrexate, for example, 10 mg/m2 body surface area on days 1, 3, 6, and 11 after marrow infusion [43] or cyclosporine plus prednisone [44, 45]. Cyclosporine is usually given for 3 to 6 months with gradual tapering if GVHD is not present. Exact dosing schedules differ from center to center, including daily duration of infusion (1, 4, or 24 hours) and the use of parenteral and oral forms [46]. Cyclosporine therapy sometimes causes renal toxicity, and doses should be reduced if renal dysfunction develops, but the serum creatinine level at which this toxicity occurs and the degree of adjustment of cyclosporine dose are not well defined and vary with the individual institutions experiences [47, 48]. Hypertension is a recognized toxicity of cyclosporine and occurs more frequently with concurrent hypomagnesemia [49]. Many neurologic abnormalities have also been reported [50], and syndromes resembling thrombotic thrombocytopenia purpura and the hemolytic-uremic syndrome have been seen in patients treated with cyclosporine, especially with concurrent hypomagnesemia [51, 52]. Mild neurologic manifestations such as tremors improve with dose reduction, but severe neurologic findings may necessitate discontinuation of cyclosporine therapy. Hepatic complications related to cyclosporine toxicity are less clearly documented than some of the other toxicities. Cyclosporine must never be abruptly discontinued because lack of tapering is frequently associated with the onset of GVHD. There is no safe range of the drug where efficacy can be ensured (that is, prevention of GVHD without toxicity such as renal injury), and no rigid guidelines for cyclosporine blood concentrations can be put forth. Despite this, most centers test extensively for cyclosporine concentration in serum or whole blood to adjust doses of cyclosporine if renal or hepatic failure occurs and to monitor treatment when switching patients from intravenous to oral preparations [46, 53]. Other commonly used regimens for GVHD prophylaxis include high-dose corticosteroids, methotrexate, and antithymocyte globulin, used alone or more commonly in combination with other agents, and, more recently, experimental agents such as an anti-CD5 murine monoclonal antibody conjugated to ricin A chain (XomaZyme, XOMA Corporation; Berkeley, California) or FK506, a newer, more potent cyclosporine-like immunosuppressive agent [54]. The other major technique to prevent GVHD