Christian Recher

Improved survival in cancer patients requiring mechanical ventilatory support: Impact of noninvasive mechanical ventilatory support

OBJECTIVE When a cancer patient becomes critically ill, mechanical ventilation (MV) is often considered futile. However, recent studies have found that outcomes of critically ill cancer patients have been improving over the years and that classic predictors of high mortality have lost their relevance. DESIGN We retrospectively determined outcomes and predictors of 30-day mortality in 237 mechanically-ventilated cancer patients admitted to the intensive care unit (ICU). PATIENTS The 132 (55.7%) patients who were admitted between 1990 and 1995 were compared with 105 (44.3%) patients who were admitted between 1996 and 1998. The malignancy was leukemia/lymphoma in 119 (50.3%) patients, myeloma in 50 (21%), and a solid tumor in 68 (28.7%). Forty-two (17.7%) patients had bone marrow transplantation, and 91 (38.4%) were neutropenic. Median Simplified Acute Physiology Score II (SAPS II) was 58 (range, 40-75). Reasons for MV were acute hypoxemic respiratory failure in 148 (62.5%) patients, coma in 54 (22.8%), and cardiogenic pulmonary edema in 35 (14.7%). Conventional MV was used first in 189 (79.8%) patients, and noninvasive MV (NIMV) was used in 48 (20.2%). Overall mortality rate was 72.5% (172 deaths). RESULTS Logistic regression identified three variables associated with mortality: ICU admission between 1996 and 1998 (odds ratio [OR], 0.24; 95% confidence interval [CI], 0.12-0.50) and the use of NIMV (OR, 0.34; 95% CI, 0.16-0.73) were protective, and the SAPS II was aggravating (OR, 1.04 per point; 95% CI, 1.02-1.06). To better define the impact of NIMV, we performed a pairwise-matched exposed-unexposed analysis. Forty-eight patients who did and 48 who did not receive NIMV as the first ventilation method were matched for SAPS II, type of malignancy, and period of ICU admission. Crude ICU mortality rates from exposed patients and controls were 43.7% and 70.8%, respectively. NIMV remained protective from mortality after adjustment for matching variables (OR, 0.31; 95% CI, 0.12-0.82). CONCLUSION Our results confirm that mortality has improved over the past decade in critically ill cancer patients, even those who require MV, and suggest that this may be, in part, because of a protective effect of NIMV.

International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts

This multicenter, randomized, open-label, phase 3 trial evaluated azacitidine efficacy and safety vs conventional care regimens (CCRs) in 488 patients age ≥65 years with newly diagnosed acute myeloid leukemia (AML) with >30% bone marrow blasts. Before randomization, a CCR (standard induction chemotherapy, low-dose ara-c, or supportive care only) was preselected for each patient. Patients then were assigned 1:1 to azacitidine (n = 241) or CCR (n = 247). Patients assigned to CCR received their preselected treatment. Median overall survival (OS) was increased with azacitidine vs CCR: 10.4 months (95% confidence interval [CI], 8.0-12.7 months) vs 6.5 months (95% CI, 5.0-8.6 months), respectively (hazard ratio [HR] was 0.85; 95% CI, 0.69-1.03; stratified log-rank P = .1009). One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively (difference, 12.3%; 95% CI, 3.5%-21.0%). A prespecified analysis censoring patients who received AML treatment after discontinuing study drug showed median OS with azacitidine vs CCR was 12.1 months (95% CI, 9.2-14.2 months) vs 6.9 months (95% CI, 5.1-9.6 months; HR, 0.76; 95% CI, 0.60-0.96; stratified log-rank P = .0190). Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features. Adverse events were consistent with the well-established safety profile of azacitidine. Azacitidine may be an important treatment option for this difficult-to-treat AML population. This trial was registered at www.clinicaltrials.gov as #NCT01074047.

Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine

Prognostic factors for response and survival in higher-risk myelodysplastic syndrome patients treated with azacitidine (AZA) remain largely unknown. Two hundred eighty-two consecutive high or intermediate-2 risk myelodysplastic syndrome patients received AZA in a compassionate, patient-named program. Diagnosis was RA/RARS/RCMD in 4%, RAEB-1 in 20%, RAEB-2 in 54%, and RAEB-t (AML with 21%-30% marrow blasts) in 22%. Cytogenetic risk was good in 31%, intermediate in 17%, and poor in 47%. Patients received AZA for a median of 6 cycles (1-52). Previous low-dose cytosine arabinoside treatment (P = .009), bone marrow blasts > 15% (P = .004), and abnormal karyotype (P = .03) independently predicted lower response rates. Complex karyotype predicted shorter responses (P = .0003). Performance status ≥ 2, intermediate- and poor-risk cytogenetics, presence of circulating blasts, and red blood cell transfusion dependency ≥ 4 units/8 weeks (all P < 10(-4)) independently predicted poorer overall survival (OS). A prognostic score based on those factors discriminated 3 risk groups with median OS not reached, 15.0 and 6.1 months, respectively (P < 10(-4)). This prognostic score was validated in an independent set of patients receiving AZA in the AZA-001 trial (P = .003). Achievement of hematological improvement in patients who did not obtain complete or partial remission was associated with improved OS (P < 10(-4)). In conclusion, routine tests can identify subgroups of patients with distinct prognosis with AZA treatment.

Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rγc-deficient mice

Human leukemic stem cells, like other cancer stem cells, are hypothesized to be rare, capable of incomplete differentiation, and restricted to a phenotype associated with early hematopoietic progenitors or stem cells. However, recent work in other types of tumors has challenged the cancer stem cell model. Using a robust model of xenotransplantation based on NOD/SCID/IL2Rγc-deficient mice, we confirmed that human leukemic stem cells, functionally defined by us as SCID leukemia-initiating cells (SL-ICs), are rare in acute myelogenous leukemia (AML). In contrast to previous results, SL-ICs were found among cells expressing lineage markers (i.e., among Lin+ cells), CD38, or CD45RA, all markers associated with normal committed progenitors. Remarkably, each engrafting fraction consistently recapitulated the original phenotypic diversity of the primary AML specimen and contained self-renewing leukemic stem cells, as demonstrated by secondary transplants. While SL-ICs were enriched in the Lin-CD38- fraction compared with the other fractions analyzed, SL-ICs in this fraction represented only one-third of all SL-ICs present in the unfractionated specimen. These results indicate that human AML stem cells are rare and enriched but not restricted to the phenotype associated with normal primitive hematopoietic cells. These results suggest a plasticity of the cancer stem cell phenotype that we believe has not been previously described.

Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure

PURPOSE Azacitidine (AZA) is the current standard of care for high-risk (ie, International Prognostic Scoring System high or intermediate 2) myelodysplastic syndrome (MDS), but most patients will experience primary or secondary treatment failure. The outcome of these patients has not yet been described. PATIENTS AND METHODS Overall, 435 patients with high-risk MDS and former refractory anemia with excess blasts in transformation (RAEB-T) were evaluated for outcome after AZA failure. The cohort of patients included four data sets (ie, AZA001, J9950, and J0443 trials and the French compassionate use program). RESULTS The median follow-up after AZA failure was 15 months. The median overall survival was 5.6 months, and the 2-year survival probability was 15%. Increasing age, male sex, high-risk cytogenetics, higher bone marrow blast count, and the absence of prior hematologic response to AZA were associated with significantly worse survival in multivariate analysis. Data on treatment administered after AZA failure were available for 270 patients. Allogeneic stem-cell transplantation and investigational agents were associated with a better outcome when compared with conventional clinical care. CONCLUSION Outcome after AZA failure is poor. Our results should serve as a basis for designing second-line clinical trials in this population.

Expression and prognostic significance of survivin in de novo acute myeloid leukaemia

Survivin is an inhibitor of apoptosis (programmed cell death) overexpressed in various human cancers, but undetectable in normal differentiated tissues. A potential distribution and prognostic significance of survivin in patients with de novo acute myeloid leukaemia (AML) was investigated. By immunofluoresence of bone‐marrow specimens and peripheral blood mononuclear cells, survivin was detected in 75 out of 125 interpretable AML cases (60%), with reactivity in 50–90% of AML cells. Survivin expression correlated with a lower white blood cell count (WBC) (P = 0·008 by the Mann–Whitney test) and was associated, in the 55 cases of FAB M0/M1/M2, with leukaemic granulocytic maturation (one out of five M/L0, 11 out of 22 M/L1 and 23 out of 28M/L2; P = 0·007 by the Fisher test). In 69 patients treated with the Acute Leukaemia French Association (ALFA) 9000 protocol, survivin expression was significantly associated with a lower WBC (P = 0·03 by the Mann–Whitney test) and favourable/intermediate cytogenetics (P = 0·03 by the Fisher test). There was no significant difference in complete remission rate or overall survival between survivin‐positive and survivin‐negative AML patients (P = 0·15 by the log‐rank test). However, survivin expression became an independent negative prognostic factor for survival when adjusted with the Cox model for established prognostic factors in AML (cytogenetics, age and WBC) or for the ALFA 9000 treatment arm (RR = 2·8 and P = 0·026, by the likelihood‐ratio test). These data suggest that survivin expression may be considered as a new unfavourable prognostic factor of de novo AML and suggest a role for apoptosis inhibition in influencing disease outcome.

Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience

Acute promyelocytic leukemia (APL) is highly curable with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT), but very long-term results of this treatment, when CT should be added to ATRA and the role of maintenance treatment, remain uncertain. In our APL93 trial that included 576 newly diagnosed APL patients, with a median follow-up of 10 years, 10-year survival was 77%. Maintenance treatment significantly reduced 10-year cumulative incidence of relapses, from 43.2% to 33%, 23.4%, and 13.4% with no maintenance, maintenance using intermittent ATRA, continuous 6 mercaptopurine plus methotrexate, and both treatments, respectively (P < .001). Maintenance particularly benefited patients with white blood cell (WBC) count higher than 5 x 10(9)/L (5000/microL). Early addition of CT to ATRA significantly improved 10-year event-free survival (EFS), but without significant effect on overall survival (OS). The 10-year cumulative incidence of deaths in complete response (CR), resulting mainly from myelosuppression, was 5.7%, 15.4%, and 21.7% in patients younger than 55, 55 to 65, and older than 65 years, respectively, supporting the need for less myelosuppressive treatments, particularly for consolidation therapy. This study is registered at http://clinicaltrials.gov as NCT00599937.

Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia

Not all patients with core binding factor acute myeloid leukemia (CBF-AML) display a good outcome. Modern risk factors include KIT and/or FLT3 gene mutations and minimal residual disease (MRD) levels, but their respective values have never been prospectively assessed. A total of 198 CBF-AML patients were randomized between a reinforced and a standard induction course, followed by 3 high-dose cytarabine consolidation courses. MRD levels were monitored prospectively. Gene mutations were screened at diagnosis. Despite a more rapid MRD decrease after reinforced induction, induction arm did not influence relapse-free survival (RFS) (64% in both arms; P = .91). Higher WBC, KIT, and/or FLT3-ITD/TKD gene mutations, and a less than 3-log MRD reduction after first consolidation, were associated with a higher specific hazard of relapse, but MRD remained the sole prognostic factor in multivariate analysis. At 36 months, cumulative incidence of relapse and RFS were 22% vs 54% (P < .001) and 73% vs 44% (P < .001) in patients who achieved 3-log MRD reduction vs the others. These results suggest that MRD, rather than gene mutations, should be used for future treatment stratifications in CBF-AML patients. This trial was registered at EudraCT as #2006-005163-26 and at www.clinicaltrials.gov as #NCT 00428558.

Changing use of intensive care for hematological patients: the example of multiple myeloma.

Objective: Intensivists generally view patients with hematological malignancies as poor candidates for intensive care. Nevertheless, hematologists have recently developed more aggressive treatment protocols capable of achieving prolonged complete remissions in many of these patients. This change mandates a reappraisal of indications for ICU admission in each type of hematological disease. Improved knowledge of the prognosis is of assistance in making treatment decisions. Patients and methods: The records of 75 myeloma patients consecutively admitted to our ICU between 1992 and 1998 were reviewed retrospectively and predictors of 30-day mortality were identified using stepwise logistic regression. Results: The median age was 56 years (37–84). Chronic health status (Knaus scale) was C or D in 39 cases. Fifty-five patients (73 %) had stage III disease and 17 had a complete or partial remission. Autologous bone marrow transplantation had been performed in 28 patients (37 %). ICU admission occurred between 1992 and 1995 in 41 patients (54.7 %), and between 1996 and 1998 in 34 patients (45.3 %). The median SAPS II and LOD scores were 60 (23–107) and 7 (0–21), respectively. Reasons for ICU admission were acute respiratory failure in 39 patients (52 %) and shock in 31 (41 %). Forty-six patients (61 %) required mechanical ventilation. Fifty patients (66 %) received vasopressors and 24 dialysis. Thirty-day mortality was 57 %. Only five parameters were independently associated with 30-day mortality in the multivariate model: female gender (OR = 5.12), mechanical ventilation (OR = 16.7) and use of vasopressor agents (OR = 5.67) were associated with a higher mortality rate, whereas disease remission (OR = 0.16) and ICU admission between 1996 and 1998 (OR = 0.09) were associated with a lower one. Conclusion: The prognosis for myeloma patients in the ICU is improving over time. This may reflect either recent therapeutic changes in hematological departments and ICUs or changes in patient selection for ICU admission. Hematologists and intensivists should work closely together to select hematological patients likely to benefit from ICU admission.

Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials

BACKGROUND Gemtuzumab ozogamicin was the first example of antibody-directed chemotherapy in cancer, and was developed for acute myeloid leukaemia. However, randomised trials in which it was combined with standard induction chemotherapy in adults have produced conflicting results. We did a meta-analysis of individual patient data to assess the efficacy of adding gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia. METHODS We searched PubMed for reports of randomised controlled trials published in any language up to May 1, 2013, that included an assessment of gemtuzumab ozogamicin given to adults (aged 15 years and older) in conjunction with the first course of intensive induction chemotherapy for acute myeloid leukaemia (excluding acute promyelocytic leukaemia) compared with chemotherapy alone. Published data were supplemented with additional data obtained by contacting individual trialists. The primary endpoint of interest was overall survival. We used standard meta-analytic techniques, with an assumption-free (or fixed-effect) method. We also did exploratory stratified analyses to investigate whether any baseline features predicted a greater or lesser benefit from gemtuzumab ozogamicin. FINDINGS We obtained data from five randomised controlled trials (3325 patients); all trials were centrally randomised and open label, with overall survival as the primary endpoint. The addition of gemtuzumab ozogamicin did not increase the proportion of patients achieving complete remission with or without complete peripheral count recovery (odds ratio [OR] 0·91, 95% CI 0·77-1·07; p=0·3). However, the addition of gemtuzumab ozogamicin significantly reduced the risk of relapse (OR 0·81, 0·73-0·90; p=0·0001), and improved overall survival at 5 years (OR 0·90, 0·82-0·98; p=0·01). At 6 years, the absolute survival benefit was especially apparent in patients with favourable cytogenetic characteristics (20·7%; OR 0·47, 0·31-0·73; p=0·0006), but was also seen in those with intermediate characteristics (5·7%; OR 0·84, 0·75-0·95; p=0·005). Patients with adverse cytogenetic characteristics did not benefit (2·2%; OR 0·99, 0·83-1·18; p=0·9). Doses of 3 mg/m(2) were associated with fewer early deaths than doses of 6 mg/m(2), with equal efficacy. INTERPRETATION Gemtuzumab ozogamicin can be safely added to conventional induction therapy and provides a significant survival benefit for patients without adverse cytogenetic characteristics. These data suggest that the use of gemtuzumab ozogamicin should be reassessed and its licence status might need to be reviewed. FUNDING None.Background Gemtuzumab Ozogamicin (GO) was the first example of antibody directed chemotherapy in cancer and developed for Acute Myeloid Leukaemia. Its role has been unclear. Five randomised trials where it was combined with standard induction chemotherapy in adults have produced different results. In an effort to clarify the level of benefit, if any, and in which patients outcomes might be improved, an individual patient data meta-analysis of these 5 trials has been undertaken.