Biomedical subjects
C A Schiffer
Publications and source records attributed to C A Schiffer.
Granulocyte transfusion therapy.
Transfusions of granulocytes have been used for many decades to treat serious infections in patients with sustained periods of granulocytopenia. The benefit has been limited somewhat by the technical problems of obtaining adequate doses of granulocytes from normal donors and by histocompatibility issues in alloimmunized recipients. The introduction of granulocyte colony-stimulating factor (G-CSF) as a means to induce granulocytosis in donors has rekindled interest in this therapy, particularly for the treatment of invasive fungal infections. Granulocyte yields after G-CSF stimulation are routinely 3 to 4 times higher than have been used in the past and have resulted in posttransfusion increments for more than 24 hours after transfusion. Studies in progress should help define the utility of these higher dose transfusions in patients with infections refractory to antibiotic therapy.
Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype.
Advances in the treatment of acute myeloid leukemia (AML) have occurred with the introduction of new therapies including high-dose cytarabine and the identification of powerful prognostic factors such as cytogenetics that predict for long-term outcome. To date, the prognostic impact of cytarabine dose escalation within various cytogenetic groups of AML has not been assessed. We describe 285 newly diagnosed patients with primary AML who had adequate karyotypes and were enrolled on a prospective Cancer and Leukemia Group B cytogenetic study. All patients were randomly assigned to postremission treatment with standard-, intermediate-, or high-dose cytarabine intensification. Patients were categorized to one of three cytogenetic groups: (a) core binding factor type [(CBF); ie., t(8;21) inv(16), t(16;16), and del(16)]; (b) normal; and (c) other abnormality karyotype. An evaluation of these patients after a median follow-up time of over 7 years was performed to determine the relationship of intensification to outcome by cytogenetic group. Patients included 57 patients with CBF AML, 140 patients with normal karyotype AML, and 88 patients with other cytogenetic abnormalities. The treatment outcome of CBF AML patients was superior, with an estimated 50% still in complete remission (CR) after 5 years as compared with 32 and 15% for patients with normal karyotype AML and other abnormality AML, respectively (P < 0.001). Univariate analysis showed the following nonkaryotype factors to predict a prolonged CR duration: (a) younger age (P < 0.008); (b) lower leukocyte count (P=0.01); (c) the presence of Auer rods (P=0.004); (d) a lower percentage of bone marrow blasts (P=0.001) at the time of diagnosis, (e) and a higher postremission cytarabine dose (P < 0.001). The impact of cytarabine dose on long-term remission was most marked (P < 0.001) in the CBF AML group (after 5 years, 78% of those with a dose of 3 g/m2 were still in CR, 57% of those with a dose of 400 mg/m2 were still in CR, and 16% of those with a dose of 100 mg/m2 were still in CR) followed by normal karyotype AML (P=0.01; after 5 years, 40% of those with a dose of 3 g/m2 were still in CR, 37% of those with a dose of 400 mg/m2 were still in CR, and 20% of those with a dose of 100 mg/m2 were still in CR). In contrast, cytarabine at all doses produced only a 21% or less chance of long-term continuous CR for patients with other cytogenetic abnormalities. A multivariate analysis of CR duration assessed the independent impact of each of these variables on cure. Significant factors entering this model in descending order of importance were cytogenetic group (CBF > normal > other abnormality; P=0.00001), cytarabine dose (3 g/m2 > 400 mg/m2 > 100 mg/m2; P=0.00001), logarithm of leukocyte count at the time of diagnosis (P=0.0005), and histological subtype of AML (P=0.005). This study demonstrates that the curative impact of cytarabine intensification varies significantly among cytogenetic groups and results in a substantial prolongation of CR among patients with CBF and normal karyotypes, but not in those with other karyotypic abnormalities. These findings support the use of pretreatment cytogenetics in risk stratification of postremission AML therapy.
A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111.
Recombinant human granulocyte colony-stimulating factor (G-CSF; filgrastim) shortens the time to neutrophil recovery after intensive chemotherapy, but its role in the treatment of adults with acute lymphoblastic leukemia (ALL) is uncertain. We randomly assigned 198 adults with untreated ALL (median age, 35 years; range, 16 to 83) to receive either placebo or G-CSF (5 microgram/kg/d) subcutaneously, beginning 4 days after starting intensive remission induction chemotherapy and continuing until the neutrophil count was >/=1, 000/microL for 2 days. The study assignment was unblinded as individual patients achieved a complete remission (CR). Patients initially assigned to G-CSF then continued to receive G-CSF through 2 monthly courses of consolidation therapy. Patients assigned to placebo received no further study drug. The median time to recover neutrophils >/=1,000/microL during the remission induction course was 16 days (interquartile range [IQR], 15 to 18 days) for the patients assigned to receive G-CSF and 22 days (IQR, 19 to 29 days) for the patients assigned to placebo (P < .001). Patients in the G-CSF group had significantly shorter durations of neutropenia (<1, 000/microL) and thrombocytopenia (<50,000/microL) and fewer days in the hospital (median, 22 days v 28 days; P = .02) compared with patients receiving placebo. The patients assigned to receive G-CSF had a higher CR rate and fewer deaths during remission induction than did those receiving placebo (P = .04 by the chi-square test for trend). During Courses IIA and IIB of consolidation treatment, patients in the G-CSF group had significantly more rapid recovery of neutrophils >/=1,000/microL than did the control group by approximately 6 to 9 days. However, the patients in the G-CSF group did not complete the planned first 3 months of chemotherapy any more rapidly than did the patients in the placebo group. Overall toxicity was not lessened by the use of G-CSF. After a median follow-up of 4. 7 years, there were no significant differences in either the disease-free survival (P = .53) or the overall survival (P = .25) for the patients assigned to G-CSF (medians, 2.3 years and 2.4 years, respectively) compared with those assigned to placebo (medians, 1.7 and 1.8 years, respectively). Adults who received intensive chemotherapy for ALL benefited from G-CSF treatment, but its use did not markedly affect the ultimate outcome.
Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics.
Approximately 45% of adults with acute myeloid leukemia (AML) have normal cytogenetics and therefore lack structural abnormalities that can assist in the localization and characterization of molecular defects. The partial tandem duplication of the ALL1 (MLL) gene has been found in several such cases of AML, yet its frequency and clinical significance are unclear. We performed Southern analysis of the ALL1 gene in pretreatment samples from 98 AML patients with normal cytogenetics. Eleven of 98 such patients (11%; 95% confidence interval, 6-19%) showed rearrangement of ALL1 at diagnosis. The partial tandem duplication of ALL1 was responsible for ALL1 rearrangement in all such cases examined, making it a frequent molecular defect in adult AML patients with normal cytogenetics. Furthermore, patients with ALL1 rearrangement had a significantly shorter duration of complete remission when compared to patients without ALL1 rearrangement (P = 0.01; median, 7.1 versus 23.2 months). This defect defines for the first time a subset of AML patients with normal cytogenetics who have short durations of complete remission and thus require new therapeutic approaches.
Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow transplants in adults with acute lymphoblastic leukemia in first remission.
BACKGROUND: There is controversy over whether high-dose therapy and a bone marrow transplant is better than conventional-dose chemotherapy in adults with acute lymphoblastic leukemia (ALL) in first remission. This decision may depend on which type of donor is available: an HLA-identical sibling, an alternative donor transplant (HLA-matched related or unrelated people other than HLA-identical siblings), or autotransplant. OBJECTIVE: To determine the appropriate use of high-dose therapy and bone marrow transplants in ALL in first remission. Develop a treatment algorithm. PANELISTS: Nine leukemia experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of acute lymphoblastic leukemia and chemotherapy and/or transplants. CONSENSUS PROCESS: We used a modified Delphi-panel group judgment process. Age, white blood cell (WBC) count, cytogenetics and immune type were permuted to define 48 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional-dose chemotherapy on a 9-point ordinal scale (1, most inappropriate; 9, most appropriate) considering three types of donors: (1) HLA-identical siblings; (2) alternative donors; and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of comparable settings and a treatment algorithm was developed. CONCLUSIONS: In people with an HLA-identical sibling donor, transplants were rated appropriate in those with unfavorable cytogenetics and uncertain in all other settings. An HLA-identical sibling donor was always preferred to an alternative donor or autotransplant. In people without an HLA-identical sibling but with an alternative donor, this type of transplant was rated appropriate in those with unfavorable cytogenetics. However, an autotransplant was preferred over an alternative donor transplant in all other settings where a transplant was rated uncertain. In people without an HLA-identical sibling or alternative donor, autotransplants were rated uncertain in all settings except in those with not unfavorable cytogenetics, WBC < 100 x 10(9) l(-1) and T- or pre-B-cell type where they were rated inappropriate.
An evaluation of combinations of diaziquone, etoposide and mitoxantrone in the treatment of adults with relapsed or refractory acute myeloid leukemia: results of 8722, a randomized phase II study conducted by Cancer and Leukemia Group B.
A phase II trial was conducted to determine which of the three possible two-drug combinations of diaziquone, etoposide and mitoxantrone was associated with the highest response rate in patients with relapsed or refractory acute myeloid leukemia (AML). Of the 167 patients (median age 55) with AML who entered the trial, 123 were in first relapse, 22 were in second relapse and 22 had failed to achieve complete remission (CR). CR rates were 30% for diaziquone and mitoxantrone, and 23% for the other two combinations (mitoxantrone/etoposide and diaziquone/etoposide), NS. Patients in first relapse had higher CR rates (40%) than other patients. Of the 166 patients who actually received treatment, 43 died before having either a CR or persistent leukemia. Non-hematologic toxicity was primarily mucosal with 24% of patients experiencing grade 3 or greater stomatitis on the two diaziquone arms, and 43% on the mitoxantrone/etoposide arm. The combination of diaziquone and mitoxantrone was selected for further testing in patients with AML.
Acute myeloid leukemia with 11q23 translocations: myelomonocytic immunophenotype by multiparameter flow cytometry.
11q23 translocations (t(11q23)) are recurring cytogenetic abnormalities in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia, involving the same gene, ALL1 (or MLL). Mixed lineage antigen expression has been reported in these leukemias, but its frequency and clinical significance are unknown. We immunophenotyped leukemia cells from 19 adult de novo AML patients with t(11q23) by multiparameter flow cytometry. Translocations included t(6;11)(q27;q23), t(9;11)(p22;q23), t(9;11;19)(p22;q23;q13.3), t(2;11)(11;17)(q37;q11q23;q11), t(11;17)(q23;q25), t(11;19)(q23;p13.1), t(11;19)(q23;p13.3) and t(11;22)(q23;q11). FAB types were M4 and M5. The committed stem cell and myeloid antigens HLADr, CD4dim, CD11b, CD13, CD15, CD32, CD33, CD38 and CD64 were each expressed in 80-100% of cases, and the early stem cell and lymphoid antigens CD34, CD56, CD3, CD2 and CD7 in 42, 39, 16, 5 and 5%, respectively. Antigen expression frequencies did not differ from those in 443 adequately karyotyped M4 and M5 cases without t(11q23). Fifteen patients (79%) attained complete remission (CR); median CR duration and survival were 10.0 and 15.1 months. CR duration and survival did not correlate with antigen expression. In particular, patients with t(9;11) survived longer than those with other t(11q23) (median not reached vs 7.6 months; P = 0.048), but antigen expression did not differ in the two groups. Thus frequencies of lymphoid antigen expression are similar in AML with t(11q23) and in other FAB M4 and M5 cases, treatment outcome does not differ in t(11q23) cases with and without lymphoid antigen expression, and better outcome of patients with t(9;11) compared to other t(11q23) does not correlate with differences in antigen expression. Mixed lineage antigen expression is not a distinctive feature of AML with t(11q23).
Hypersensitivity reactions to L-asparaginase do not impact on the remission duration of adults with acute lymphoblastic leukemia.
Among its multiple toxic effects, L-asparaginase induces allergic reactions that may reduce its biological effect. The impact of hypersensitivity reactions on the duration of leukemia-free survival (LFS) was assessed in adults with newly diagnosed acute lymphoblastic leukemia (ALL) receiving intensive multi-agent chemotherapy. In CALGB study 8811 (Blood 1995; 85: 2025-2037), 197 adults were scheduled to receive 14 doses of Escherichia coil L-asparaginase (6000 U/m2 SC) during 7 of the first 12 weeks of chemotherapy. No further L-asparaginase was given. Chemotherapy was given for 24 months. The median follow-up time has been 5.7 years. Of the 141 patients who remained on study after 12 weeks, 82 (58%) had received all 14 planned doses; 38 (27%) had 12-13 L-asparaginase doses documented in their treatment record; 21 (15%) patients had received < or =11 doses due to a variety of toxic effects. The mean number of doses received prior to experiencing any hypersensitivity reaction was seven (range 1-11). Seven patients had mild hypersensitivity reactions, but all seven eventually received 12-14 doses of E. coil L-asparaginase. Twenty-one other patients had severe hypersensitivity reactions that required discontinuation of E. coil L-asparaginase; 20 of these patients were switched to Erwinia L-asparaginase to complete their treatment. Ultimately, 12 of these 20 patients received 14 doses of L-asparaginase in total, and six received 12-13 doses. Thus, only three of the 21 patients who had severe hypersensitivity reactions received < or =11 total L-asparaginase doses. Other L-asparaginase-related complications included pancreatitis (15 patients), hypofibrinogenemia <100mg/dl (29 patients), and deep venous thrombosis or pulmonary embolism (eight patients); some of these patients had L-asparaginase discontinued after these complications. The estimates for LFS at 3 years were 55% (95% confidence interval, 44-65%) for the patients who received all 14 L-asparaginase doses (median LFS, 5.1 years), 47% (95% CI, 33-62%) for those who received 12-13 doses, and 48% (95% CI, 29-67%) for those who received < or =11 doses. There were no significant differences between these three groups in the length of LFS (P=0.68). LFS did not correlate with a history of severe hypersensitivity reaction (P=0.67). In general, E. coil L-asparaginase was well tolerated in these adult patients, and most patients received all of the planned therapy. Patients who had mild L-asparaginase hypersensitivity reactions and patients who switched to Erwinia L-asparaginase because of more severe allergic reactions did not have significantly shorter LFS than the remaining adults treated on this ALL protocol. The possibility that E. coli L-asparaginase is inactivated or destroyed in those individuals who have become hypersensitive to it becomes less important when allergic patients are secondarily treated with Erwinia L-asparaginase.
Clinical characteristics of patients with de novo acute myeloid leukaemia and isolated trisomy 11: a Cancer and Leukemia Group B study.
Isolated trisomy 11 is the third most common sole trisomy in de novo acute myeloid leukaemia (AML). However, only 49 cases have been published, and for only a fraction of these cases has full description of clinical and haematological features been provided. As a result, little is known about the clinical characteristics of de novo AML patients with solitary trisomy 11. We have identified 13 patients (0.9%) with isolated trisomy 11 among a total of 1496 consecutive adult patients successfully karyotyped as part of a prospective Cancer and Leukemia Group B (CALGB) cytogenetic study (CALGB 8461). Nine patients (69%) were over the age of 60 (range 29-73 years). Eight patients (62%) were diagnosed with AML of FAB M2 subtype, three patients (23%) had FAB M1 AML and one patient each had AML of FAB M0 and M7, respectively. Seven patients (54%) had high, >100 x 10(9)/l, platelet counts (median 102 x 10(9)/l; range 17-207 x 10(9)/l). All patients received CALGB induction therapy with standard doses of cytarabine and daunorubicin. Six patients (46%) achieved a complete remission (CR). The median CR duration was 17.5 months (range 8.7-49.8). Only one patient, who underwent bone marrow transplantation in first CR, continues in initial CR. The median survival was 14.3 months (range 0.5-50.7); only one patient survives. We conclude that de novo AML with isolated trisomy 11 is predominantly associated with older age, M2 and M1 FAB subtypes, high platelet count and few long-term disease-free survivals, although it is currently unknown whether isolated trisomy 11 constitutes an independent prognostic factor.
The relationship between the duration of platelet storage and the development of transfusion reactions.
BACKGROUND: The incidence of platelet transfusion reactions may depend partly on the length of storage. The influence of reactions on the effectiveness of platelet transfusions is not known. STUDY DESIGN AND METHODS: Platelet transfusion reactions, identified by prospective monitoring, were analyzed for the effects of component type, recipient lymphocytotoxic antibodies, bacterial contamination, and duration of storage. Posttransfusion corrected count increments (CCIs) were used to evaluate the effectiveness of transfusions associated with reactions by comparing them to those of randomly selected transfusions without reactions. RESULTS: Reactions accompanied 4 percent of the 4926 transfusions given and included 119 febrile nonhemolytic transfusion reactions, 62 allergic reactions, and 13 reactions with features of both. Platelet concentrates contained a mean of 0.5 x 10(8) white cells per unit. Lymphocytotoxic antibodies were detectable in 20 of 84 recipients tested proximate to a reaction. Bacterial cultures from 4 of 81 units were positive; 1 unit was associated with fatal Enterobacter sp. sepsis. The incidence of febrile nonhemolytic transfusion reactions but not allergic reactions was related to platelet storage duration. The CCI was not significantly different for transfusions associated with reactions (10.97 [median, range 0-72.5; n = 165]) or not so associated (13.1 [median, range 0-39.5; n = 174]) (p = 0.08). CONCLUSION: The incidence of febrile nonhemolytic transfusion reactions but not allergic reactions appears to be related to the duration of platelet storage. Transfusion reactions may not have an adverse impact on the effectiveness of platelet transfusions.
Double esterase staining and other neutrophilic granule abnormalities in 237 patients with the myelodysplastic syndrome studied by the cancer and leukemia group B.
We investigated double (specific and nonspecific) esterase (DE) staining in marrow cells of 237 patients with the myelodysplastic syndromes (MDS). Additional abnormalities of neutrophilic granules were examined cytochemically and immunocytochemically for myeloperoxidase activity and antigen elastase, lactoferrin and CD15 granule-membrane glycoproteins. Abnormal DE staining (>/=3% of all nucleated marrow cells) was present in 27% of patients with no difference among different MDS subtypes. However, the prevalence of high abnormal DE staining (>/=10%) was significantly lower in refractory anemia with excess blasts in transformation (1%) compared to other MDS subtypes (12-15%; p = 0.004). The prevalence of other granule abnormalities was not statistically different in the DE normal and DE abnormal groups. Abnormal DE staining is relatively common among all MDS subtypes. High DE staining may identify a subgroup of patients with a lower grade MDS.
Patients with isolated trisomy 8 in acute myeloid leukemia are not cured with cytarabine-based chemotherapy: results from Cancer and Leukemia Group B 8461.
To date, neither the clinical significance of isolated trisomy 8, the most frequent trisomy in acute myeloid leukemia (AML), nor the effect of age within a single cytogenetic group has been examined. We report a large cohort of adult trisomy 8 patients and examine whether increasing age within a homogeneous cytogenetic group alters clinical outcome. Characteristics and outcome of patients with isolated trisomy 8 enrolled in the prospective Cancer and Leukemia Group B (CALGB) cytogenetic study CALGB 8461 are described. Isolated trisomy 8 was identified in 42 (3.03%) of 1387 patients enrolled in five CALGB treatment protocols. These patients had a median age of 64 (range, 16-79) years, 50% female proportion, and a low frequency of hepatomegaly (10%) or splenomegaly (10%). Laboratory features included a median white blood count of 7.3 x 10(9)/L, nonspecific French-American-British distribution, with 36% of patients having Auer rods. Treatment outcome was unsatisfactory with a complete remission (CR) rate of 59%, median CR duration of 13.6 months, and median survival of 13.1 months. Older age adversely affected outcome; trisomy 8 patients > or =60 years had both an inferior CR rate (40% versus 88%; P = 0.004) and overall survival (median, 4.8 versus 17.5 months; P = 0.01), as compared with those <60 years of age. Of the patients <60 years of age, only four remain alive, and all received noncytarabine-based intensive chemotherapy, followed in three cases by autologous (n = 2) or allogeneic (n = 1) stem cell transplant in CR1. Adults with AML and isolated trisomy 8 have a poor outcome that is accentuated by increasing age and is rarely cured with cytarabine-based therapy. Alternative investigational treatments should be considered for individuals with this AML subset.
Long-term follow-up of Cancer and Leukemia Group B studies in acute myeloid leukemia.
BACKGROUND: During the past 3 decades, the Cancer and Leukemia Group B (CALGB) has conducted numerous large clinical trials in adult patients with acute myeloid leukemia. METHODS: Updated data were obtained for 9 trials initiated by the CALGB between 1974 and 1992. The updated data were compared with the original published results. RESULTS: It was apparent from all the studies that hazard rates for death and relapse are greatest in the first year, decrease substantially between Years 1 and 2, then decrease further between Years 2 and 3. Rates of death and relapse are quite low after 3-4 years. Large numbers of patients are long-term disease free survivors. Overall, these patients have excellent function and a normal quality of life. CONCLUSIONS: Patients with AML who are in complete remission for 3-4 years can be assured that late relapse and death are relatively uncommon events. It is inadvisable to publish results of large studies until this minimal level of follow-up has been reached.
Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: a cancer and leukemia group B study.
Following reports of childhood acute myeloid leukemia (AML) showing that patients with t(9; 11)(p22; q23) have a better prognosis than those with translocations between 11q23 and other chromosomes, we compared response to therapy and survival of 24 adult de novo AML patients with t(9; 11) with those of 23 patients with other 11q23 translocations [t(11q23)]. Apart from a higher proportion of French-American-British (FAB) M5 subtype in the t(9; 11) group (83% v 43%, P = .006), the patients with t(9; 11) did not differ significantly from patients with t(11q23) in terms of their presenting clinical or hematologic features. Patients with t(9; 11) more frequently had an extra chromosome(s) 8 or 8q as secondary abnormalities (46% v 9%, P = .008). All patients received standard cytarabine and daunorubicin induction therapy, and most of them also received cytarabine-based intensification treatment. Two patients, both with t(9; 11), underwent bone marrow transplantation (BMT) in first complete remission (CR). Nineteen patients (79%) with t(9; 11) and 13 (57%) with t(11q23) achieved a CR (P = .13). The clinical outcome of patients with t(9; 11) was significantly better: the median CR duration was 10.7 versus 8.9 months (P = .02), median event-free survival was 6.2 versus 2.2 months (P = .009), and median survival was 13.2 versus 7.7 months (P = .009). All patients with t(11q23) have died, whereas seven (29%) patients with t(9; 11) remain alive in first CR. Seven of eight patients with t(9; 11) who received postremission regimens with cytarabine at a dose of 100 (four patients) or 400 mg/m2 (2 patients) or who did not receive postremission therapy (2 patients) have relapsed. In contrast, 7 (64%) of 11 patients who received intensive postremission chemotherapy with high-dose cytarabine (at a dose 3 g/m2) (5 patients), or underwent BMT (2 patients) remain in continuous CR. We conclude that the outcome of adults with de novo AML and t(9; 11) is more favorable than that of adults with other 11q23 translocations; this is especially true for t(9; 11) patients who receive intensive postremission therapy.
Quality of life for adult leukemia survivors treated on clinical trials of Cancer and Leukemia Group B during the period 1971-1988: predictors for later psychologic distress.
BACKGROUND: To identify predictors of psychosocial adjustment for survivors of adult acute leukemia, the adaptation of 206 survivors (77% with acute myelogenous leukemia, and 23% with acute lymphocytic leukemia) treated on any of 13 Cancer and Leukemia Group B trials during the period 1971-1988 was examined. METHODS: Survivors (median age, 41 years) who were at least 1 year from completion of all treatment (median, 5 years) were interviewed by telephone about psychologic symptoms; social, sexual, and vocational function; and beliefs about control over health. Standardized psychologic instruments were used to evaluate survivors' responses. RESULTS: Most survivors adapted well; however, 14% were 1.5 standard deviations above normal on the Global Severity Index of the Brief Symptom Inventory. Predictors of greater psychologic distress included less education, younger age, anticipatory distress during chemotherapy treatment, and the combination of more medical problems after treatment with poorer family function. Anticipatory nausea and distress during chemotherapy predicted persistent visceral distress later, which occurred with reminders of treatment. Anticipatory vomiting predicted a greater tendency toward cancer-related intrusive thoughts and avoidance of reminders. CONCLUSIONS: Patients experiencing anticipatory distress during treatment who are younger and less educated should be monitored for depressive syndromes later.
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.
Expression of the neural cell adhesion molecule CD56 is associated with short remission duration and survival in acute myeloid leukemia with t(8;21)(q22;q22).
Although acute myeloid leukemia (AML) with t(8;21) (q22;q22) is associated with a high complete remission (CR) rate and prolonged disease-free survival, treatment outcome is not universally favorable. Identifying factors that predict for treatment outcome might allow therapy to be optimized based on risk. AML with t(8;21) has a distinctive immunophenotype, characterized by expression of the myeloid and stem cell antigens CD13, CD15, CD34, and HLADr, and frequent expression of the B-cell antigen CD19 and the neural cell adhesion molecule CD56, a natural killer cell/stem cell antigen. Because CD56 expression has been associated with both extramedullary leukemia and multidrug resistance, we sought to correlate CD56 expression with treatment outcome in AML with t(8;21). Pretreatment leukemia cells from 29 adult de novo AML patients with t(8;21) treated on Cancer and Leukemia Group B (CALGB) protocols were immunophenotyped by multiparameter flow cytometry as part of a prospective immunophenotyping study of adult AML (CALGB 8361). CD56 was expressed in 16 cases (55%). There was no correlation between CD56 expression and age, sex, white blood cell count, granulocyte count, the presence of additional cytogenetic abnormalities, or the presence of extramedullary disease at diagnosis. The CR rate to standard-dose cytarabine and daunorubicin was similar for cases with and without CD56 expression (88% v 92%; P = 1.0). Post-CR therapy included at least one course of high-dose cytarabine in 24 of 26 patients who achieved CR; numbers of courses administered were similar in cases with and without CD56 expression. Although post-CR therapy did not differ, CR duration was significantly shorter in cases with CD56 expression compared with those without (median, 8.7 months v not reached; P = .01), as was survival (median, 16.5 months v not reached; P = .008). We conclude that CD56 expression in AML with t(8;21) is associated with significantly shorter CR duration and survival. Our results suggest that CD56 expression may be useful in stratifying therapy for this subtype of AML.