Although it is now generally accepted that imatinib is the best initial treatment for patients newly diagnosed with chronic myeloid leukemia (CML) in chronic phase, a number of questions remain ...unanswered. For example, (1) Is imatinib the best initial treatment for every chronic-phase patient? (2) At what dose should imatinib be started? (3) How should response to treatment be monitored? (4) For how long should the drug be continued in patients who have achieved and maintain a complete molecular response? (5) How does one handle a patient who achieves a 2-log but not a 3-log reduction in BCR-ABL transcripts? (6) How should response or failure be defined? (7) For the patient deemed to have failed imatinib, should one offer dasatinib or nilotinib? (8) For the patient who has failed imatinib but has a possible allogeneic transplant donor, should one offer dasatinib or nilotinib before recommending a transplantation? (9) Should the transplantation be myeloablative or reduced intensity conditioning? (10) How should one treat the patient who relapses after allografting? This paper will address these issues, many of which cannot yet be answered definitively.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The schizophrenia spectrum disorders are neurodevelopmental illnesses with a lifetime prevalence near 1%, producing extensive functional impairment and low expectations for recovery. Until recently, ...treatment in the United States has largely attempted to stabilize individuals with chronic schizophrenia. The identification and promotion of evidence-based practices for schizophrenia via the Patient Outcomes Research Team, combined with international studies supporting the value of early intervention, provided the foundation for the Recovery After an Initial Schizophrenia Episode (RAISE) project. The RAISE studies further supported the value of reducing the duration of untreated psychosis and providing a multi-element treatment called coordinated specialty care (CSC) to improve outcomes for patients in usual treatment settings. Although CSC programs have proliferated rapidly in the United States, many challenges remain in the treatment and recovery of individuals with schizophrenia in the aftermath of RAISE.
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CMK, FFLJ, NUK, UL, UM, UPUK
Patients with splenomegaly and abnormally high leukocyte counts were first recognized in France, Germany, and Scotland in the 1840s. The only well-documented therapy in the 19th century was use of ...arsenic in one or other form, which did undoubtedly reduce the leukocyte count but probably did little or nothing to prolong life. These early cases were probably examples of chronic myeloid leukemia (CML) (then called chronic granulocytic leukemia). In the 20th century important steps in unraveling the pathogenesis of CML were the discovery of the Philadelphia chromosome in 1960, and of the (9;22) translocation in 1973. There followed definition of the breakpoint cluster region on chromosome 22 in 1984 and the demonstration of the BCR-ABL transcript in CML in 1985. In the first half of the 20th century patients were treated predominantly with radiotherapy, and later on with busulfan, hydroxycarbamide, or interferon-alfa (IFN-α). From 1980 onwards allogeneic stem cell transplantation (SCT) became the treatment of choice for eligible patients. The era of tyrosine kinase inhibitors (TKI) began in 1998 and today the use of the original TKI, imatinib, has replaced SCT as initial therapy for patients who present with CML in chronic phase.
We studied BCR-ABL1 transcript levels in patients with chronic myeloid leukemia in chronic phase (CML-CP) at 3, 6, and 12 months after starting imatinib to identify molecular milestones that would ...predict for overall survival (OS) and other outcomes more reliably than serial marrow cytogenetics.
We analyzed 282 patients with CML-CP who received imatinib 400 mg/d as first-line therapy followed by dasatinib or nilotinib if treatment with imatinib failed. We used a receiver operating characteristic curve to identify the cutoffs in transcript levels at 3, 6, and 12 months that would best predict patient outcome. We validated our findings in an independent cohort of 95 patients treated elsewhere.
Patients with transcript levels of more than 9.84% (n = 68) at 3 months had significantly lower 8-year probabilities of OS (56.9% v 93.3%; P < .001), progression-free survival, cumulative incidence of complete cytogenetic response, and complete molecular response than those with higher transcript levels. Similarly, transcript levels of more than 1.67% (n = 87) at 6 months and more than 0.53% (n = 93) at 12 months identified high-risk patients. However, transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (relative risk, 0.207; P < .001 and relative risk, 0.158; P < .001, respectively).
A single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.
Imatinib is remarkably effective in treating newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP). To date, most of the available data come from a single multicenter ...study in which some of the patients were censored for diverse reasons. Here, we report our experience in treating patients at a single institution in a setting where all events were recorded.
A total of 204 consecutive adult patients with newly diagnosed CML in CP received imatinib from June 2000 until August 2006. Response (hematologic, cytogenetic, and molecular), progression-free survival (PFS) and survival were evaluated.
At 5 years, cumulative incidences of complete cytogenetic response (CCyR) and major molecular response (MMR) were 82.7% and 50.1%, respectively. Estimated overall survival and PFS were 83.2% and 82.7%, respectively. By 5 years, 25% of patients had discontinued imatinib treatment because of an unsatisfactory response and/or toxicity. The 5-year probability of remaining in major cytogenetic response while still receiving imatinib was 62.7%. Patients achieving a CCyR at 1 year had a better PFS and overall survival than those failing to reach CCyR, but achieving a MMR conferred no further advantage. The identification of a kinase domain mutation was the only factor predicting for loss of CCyR.
Imatinib is highly effective in most patients with CML-CP; patients who respond are likely to live substantially longer than those treated with earlier therapies. Achieving CCyR correlated with PFS and overall survival, but achieving MMR had no further predictive value. However, approximately one third of patients still need better therapy.
Two case series examining the impact of convalescent plasma on patients with COVID-19 suggest some clinical benefit from early administration and modest impact on parameters of inflammation. Further ...assessment of the impact of this intervention awaits controlled clinical trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This study examines the prognostic significance of early molecular response using an expanded dataset in chronic myeloid leukemia patients enrolled in the International Randomized Study of Interferon ...and STI571 (IRIS). Serial molecular studies demonstrate decreases in BCR-ABL transcripts over time. Analyses of event-free survival (EFS) and time to progression to accelerated phase/blast crisis (AP/BC) at 7 years were based on molecular responses using the international scale (IS) at 6-, 12-, and 18-month landmarks. Patients with BCR-ABL transcripts > 10% at 6 months and > 1% at 12 months had inferior EFS and higher rate of progression to AP/BC compared with all other molecular response groups. Conversely, patients who achieved major molecular response MMR: BCR-ABL (IS) ≤ 0.1% by 18 months enjoyed remarkably durable responses, with no progression to AP/BC and 95% EFS at 7 years. The probability of loss of complete cytogenetic response by 7 years was only 3% for patients in MMR at 18 months versus 26% for patients with complete cytogenetic response but not MMR (P < .001). This study shows a strong association between the degree to which BCR-ABL transcript numbers are reduced by therapy and long-term clinical outcome, supporting the use of time-dependent molecular measures to determine optimal response to therapy. This study is registered at www.clinicaltrials.gov as NCT00006343.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background Preoperative chemotherapy is a strategy for conversion to resection and/or assessing disease biology prior to operation. The utility of such an approach in gallbladder carcinoma ...(GBCA) is unknown. This study evaluates outcomes of GBCA patients treated with chemotherapy for locally advanced or lymph node involved tumors. Study Design Patients that received systemic chemotherapy for locally advanced or lymph node positive GBCA were identified from a departmental database. Patients were excluded if there was any evidence of distant metastases or if records were inadequate to determine initial chemotherapy and response. Response (RECIST), operative results, and overall survival (OS) were assessed. Results Seventy-four patients were included from 1992-2015. Eighty-nine percent of patients (n=64) were treated with gemcitabine and 57% with gemcitabine/platinum (n=42). At initial response assessment, 17 patients (23%) had progression. The remaining patients had stable disease (n=38, 51%) or partial response (n=19, 26%). Twenty-two patients (30%) underwent attempt at resection which was definitive for 10 patients (14%). Median OS for the entire cohort was 14 months (95% CI:11.3-17.9). Among patients with surgery, definitive resection was associated with a median OS of 51 months (95% CI:11.7-55.3) compared to 11 months (95% CI:4.1-23.6) for those that were unresectable (p=0.003). Conclusions Even without distant metastases, locally advanced or lymph node positive GBCA is associated with poor outcomes. Definitive resection was possible in a subset of patients selected for surgery after a favorable response to chemotherapy and was associated with long-term survival. We recommend surgical re-evaluation following chemotherapy to select potential operative candidates.
The treatment of patients with chronic myeloid leukemia (CML) must be ranked as one of the great medical success stories of the past 30 years. The demonstration that the Philadelphia (Ph) chromosome ...carries a fusion gene formed by the juxtaposition of BCR and ABL genetic sequences focused attention on the possibility that the tyrosine kinase activity of ABL might be greatly enhanced by fusion with BCR such that the BCR-ABL oncoprotein could be the primary cause of CML. If it were so, then pharmacologic inactivation of the oncoprotein might be clinically useful, and so it proved. In 1996, Druker et . . .
An international basis for comparison of BCR-ABL mRNA levels is required for the common interpretation of data derived from individual laboratories. This will aid clinical decisions for individual ...patients with chronic myeloid leukemia (CML) and assist interpretation of results from clinical studies. We aligned BCR-ABL values generated by 38 laboratories to an international scale (IS) where a major molecular response (MMR) is 0.1% or less. Alignment was achieved by application of laboratory-specific conversion factors calculated by comparisons performed with patient samples against a reference method. A validation procedure was completed for 19 methods. We determined performance characteristics (bias and precision) for consistent interpretation of MMR after IS conversion. When methods achieved an average BCR-ABL difference of plus or minus 1.2-fold from the reference method and 95% limits of agreement within plus or minus 5-fold, the MMR concordance was 91%. These criteria were met by 58% of methods. When not met, the MMR concordance was 74% or less. However, irrespective of precision, when the bias was plus or minus 1.2-fold as achieved by 89% of methods, there was good agreement between the overall MMR rates. This indicates that the IS can deliver accurate comparison of molecular response rates between clinical trials when measured by different laboratories.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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