Arthritis Australia

By S. Topork. Medical College of Wisconsin. 2018.

Definitions of response Response Definition CHR Leukocyte count of 10 109/L; platelet count 450 109/L; normal differential with no early forms; no splenomegaly MCyR 0%-35% Ph metaphases (BM) PCyR 1%-35% Ph metaphases (BM) CCyR 0% Ph metaphases (BM) MMR BCR-ABL1 IS 0 best quibron-t 400 mg. This conversion factor is de- rived from extensive validation and comparison with a reference laboratory purchase quibron-t 400mg with visa. All molecular response criteria and recommendations for intervention in the NCCN or ELN guidelines are based upon IS molecular response. Recently, the World Health Organization (WHO) has spearheaded efforts to provide accredited reference reagents directly linked to the BCR-ABL1 IS scale. These secondary reference materials are available from the Institute for Reference Materials and Measure- ments (Belgium). Supplies of these primary standards are limited, but other methods to provide reference standards are under investi- gation. The importance of universal standardized testing is reflected in the growing importance of molecular response measurements at early time points after therapy initiation, as well as in measuring MMR and deep molecular responses consistently. Unlike MMR, there are various definitions of deep molecular response (MR), including MR 4. Efforts are under way to standardize definitions and methods to reliably detect and measure such small amounts of BCR-ABL1. OS and PFS on first-line imatinib or dasatinib therapy. The 3-year OS is 97% and 97% for The growing recognition of the importance of early response is dasatinib and imatinib, respectively; 3-year PFS is 93% and 91% for reflected by recent changes to the NCCN guidelines. The reagents has made it difficult to compare results between laborato- recognition of the clinical significance of early response is not a new ries. In the absence of universal standards or reagents, the Interna- one, but several studies over the past 3 years have added increasing tional Scale (IS) was developed to harmonize molecular responses support to the idea that a very early time point, 3 months after across laboratories. A study of 1440 patients treated on the German CML IV Table 1. Definitions of AP CML Persistent thrombocytopenia Additional clonal cytogenetic AP criteria Blasts Basophils (unrelated to therapy) aberrations WHO 10%-19% 20% 100 109/L Present ELN 15%-29% 20% 100 109/L Present MD Anderson 15%-29% 20% 100 109/L Present The WHO, ELN, and MD Anderson Cancer Center definitions of AP CML are shown. The WHO AP criteria also include the following: persistent thrombocytosis ( 1000 10 /L) or leukocytosis (9 10 10 /L) or spleen size unresponsive to therapy. Basophils or blasts may be measured in peripheral blood or BM. Hematology 2013 177 study observed that among the 28% of patients who did not TKIs, these milestones occur earlier ( 3 months earlier or more) achieve 10% BCR-ABL1, OS after 5 years was poorer at 87% and also result in small improvements in PFS. A BM examination at 3 months may also be used in lieu of significantly poorer OS of 56. These observations suggested that 3-month molecular own practice, I am moving away from performing frequent BMs response may provide more prognostic information than 6-month examinations in patients with 10% BCR-ABL1 IS at 3 months major cytogenetic response (MCyR) or 12-month CCyR. I will perform a BM study also suggested that molecular response correlates well with aspirate at 6 months or earlier when BCR-ABL1 is 1% to cytogenetic response (ie, 10% with absence of MCyR at 3 months confirm CCyR, because this level typically correlates with CCyR at and 1% with absence of CCyR at 6 months). For standard dose IM-treated patients achieving 1% other studies demonstrating that early cytogenetic response corre- BCR-ABL1 IS transcripts may take longer and an argument can be lates with improved EFS,17 the newest iteration of the NCCN made (especially in laboratories with reliable IS molecular monitor- guidelines also proposes that absence of a partial cytogenetic ing) to wait up to 12 months if BCR-ABL1 transcripts are decreasing. Recent studies have determined that early response at responders when reliable molecular testing is available is limited. Unlike Ph ACA, Ph ACA does generation TKIs, lower BCR-ABL1 IS transcript thresholds may be not affect outcomes except in the rare cases of myelodysplastic more predictive given the more rapid decrease in disease burden syndrome–associated abnormalities, which are typically accompa- seen with these agents. It is possible that poor molecular response at 3 months indicated unless evidence of dysplasia is noted. Outcomes data identifies a subset of patients who respond poorly to all TKIs. The support that CCyR, or perhaps in the future a surrogate for CCyR, correlation between high-risk EUTOS Risk Score and poor early remains the gold standard of response and for some patients, such as molecular response supports this idea. I also watch closely as I do in The achievement of MMR or better is of interest for 2 reasons: patients treated with first-line TKIs for AP. I do acknowledge that achieving a stable MMR may provide a safe harbor and achieving a these data also suggest that most patients who are not switched will deep molecular response may identify a subset of patient in whom have good outcomes, but it is difficult to identify within this subset TKIs can be safely stopped. Molecular responses are associated of patients who will do better versus who will do poorly. In addition, with durability of response, loss of response, EFs, and PFS. Updates although categorical cutoffs are useful to analyze outcomes, they do of the IRIS trial demonstrated that achievement of MMR affected require a little common sense before considering a change in the durability of CCyR and that patients achieving MMR had the treatment strategy. In addition, a patient whose achieving MMR improves EFS or OS in patients achieving a BCR-ABL1 transcript level decreases from 90% to 10. Two studies investigated stopping IM in patients with deep molecu- Continued importance of a complete cytogenetic lar responses: the French STIM (MR 5. This requires reproducible and reliable eradicate stem cells in in vitro studies, mathematical modeling molecular response surrogates for cytogenetic responses.

Findings from two placebo-controlled trials were insufficient to draw conclusions purchase quibron-t 400mg amex. Comparative effectiveness No evidence Seasonal affective disorder Comparative efficacy Poor No head-to head evidence exists generic quibron-t 400mg overnight delivery. Findings from placebo-controlled trials were insufficient to draw conclusions about comparative efficacy. Comparative effectiveness No evidence Major depressive disorder in children Comparative efficacy Poor No head-to head evidence exists. Findings from placebo-controlled trials were insufficient to draw conclusions about comparative efficacy. Comparative effectiveness No evidence Generalized anxiety disorder Comparative efficacy Fair to poor Available head-to head evidence is limited to comparisons of fluoxetine with sertraline and paroxetine with escitalopram or venlafaxine. Except for one study favoring escitalopram over paroxetine, no major differences in efficacy could be detected. Comparative effectiveness No evidence Second-generation antidepressants 113 of 190 Final Update 5 Report Drug Effectiveness Review Project Key Question, Disorder, and Strength of Outcome of Interest Evidence Findings Obsesssive compulsive disorder Comparative efficacy Fair to poor Available head-to head evidence is limited to comparisons of paroxetine with escitalopram, sertraline, and venlafaxine and venlafaxine with duloxetine and escitalopram. Overall, no major differences in efficacy could be detected. Comparative effectiveness No evidence Panic disorder Comparative efficacy Fair to poor Available head-to head evidence is limited to comparisons of sertraline with citalopram, nefazodone, and venlafaxine. Overall, no major differences in efficacy between citalopram and escitalopram could be detected. The evidence on the comparative efficacy of paroxetine and venlafaxine ER is inconclusive. Comparative effectiveness No evidence Post-traumatic stress disorder Comparative efficacy Fair to poor Available head-to head evidence is limited to comparisons of sertraline with citalopram, nefazodone, and venlafaxine. Overall, no major differences in efficacy could be detected. Comparative effectiveness No evidence Social anxiety disorder Comparative efficacy Fair to poor Available head-to head evidence is limited to comparisons of paroxetine with with escitalopram and venlafaxine ER. Overall, no major differences in efficacy could be detected. Comparative effectiveness No evidence Premenstrual dysphoric and late luteal phase dysphoric disorder Comparative efficacy Poor No head-to head evidence exists. Findings from placebo-controlled trials were insufficient to draw conclusions about comparative efficacy. Comparative effectiveness No evidence Key Question 2. Comparative harms of second-generation antidepressants General tolerability Adverse events profiles Fair Adverse events profiles are similar among second-generation antidepressants. Differences in the incidence of specific adverse events exist. Diarrhea Fair Evidence from multiple fair-quality studies indicates that sertraline has a higher incidence of diarrhea than bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, and venlafaxine. Discontinuation rates Good Meta-analyses of efficacy trials indicate that overall discontinuation rates are similar. Venlafaxine has a higher rate of discontinuations because of adverse events and a lower rate of discontinuations because of lack of efficacy than SSRIs as a class. Nausea and vomiting Good Meta-analysis of 15 fair-quality studies indicates that venlafaxine has a higher rate of nausea and vomiting than SSRIs as a class. Weight change Fair Seven fair trials indicate that mirtazapine leads to higher weight gains than citalopram, fluoxetine, paroxetine, and sertraline. Severe adverse events Cardiovascular adverse events Fair No differences in risk of sudden cardiac death could be detected among citalopram, fluoxetine, and venlafaxine Fractures Poor Overall, increased risk of fractures with use of SSRIs. Evidence is insufficient to determine the comparative risk. Gastrointestinal bleeding Poor Overall, increased risk of gastrointestinal bleeding with use of SSRIs. Evidence is insufficient to determine the comparative risk. Second-generation antidepressants 114 of 190 Final Update 5 Report Drug Effectiveness Review Project Key Question, Disorder, and Strength of Outcome of Interest Evidence Findings Hepatotoxicity Poor Evidence from existing studies is insufficient to draw conclusions about the comparative risk of hepatotoxicity. Weak evidence indicates that nefazodone might have an increased risk of hepatotoxicity. Sexual adverse events Good Five fair trials provide evidence that bupropion causes significantly less sexual dysfunction than escitalopram, fluoxetine, paroxetine, and sertraline.

It lays the foundation for a struc- tured physical examination cheap 400 mg quibron-t, after which the need Menstrual history for further investigations is determined generic 400mg quibron-t amex. If possible any medical records held at the clinic should be Age at menarche and any significant menstrual read before the client enters the room. Are men- records that the client may have brought with her strual problems a current concern? The client should empty her bladder strual period and if there has been any abnormal before the physical examination, which will make bleeding since that date should be noted. Past medical, surgical and obstetric histories Abdominal examination Enquiry needs to be made about any past serious Inspection will reveal signs of previous surgery and medical illnesses, including psychiatric illness, any any obvious masses or distention. If the client is operations, HIV and sexually transmitted infec- experiencing pain prior to abdominal palpation, tions, and any pregnancies together with their out- asking her to lift her head and shoulders off the bed comes. For nulliparous women enquiry should be and enquiring whether this eases the pain or makes made about their pregnancy intentions. Are they it worse will determine whether the pain is origi- currently trying to conceive, if so, for how long nating from within the abdominal cavity or the and is failure to conceive an anxiety? Tensing the abdominal wall child is a common reason for women to make re- muscles tends to lessen intra-abdominal pain, peated visits to a health facility, especially in under- whereas the pain will be made worse if the patho- resourced countries where bearing children is 10 logy is in the abdominal wall. Abdominal palpation should commence in a Past and present contraceptive use should be re- pain-free site and proceed systematically around the corded, together with any unpleasant side-effects. Any tender areas, obvious masses It is helpful to know whether there is a history or loaded bowel should be noted. The timing of this enquiry depends on the rapport built up with the client, and it can be done Speculum examination at any appropriate time during the consultation. This is advisable for women who are sexually Although not clearly understood, there appears to active, and should always be performed if there be a relationship between chronic pelvic pain and has been post-coital bleeding, an abnormal vaginal childhood sexual abuse, especially if there is con- 6 discharge or if the client has never had their cer- tinuing abuse into adulthood. Sometimes bluish deposits of endometriosis can be seen in the posterior fornix. Cervical screening is not readily available in under- The physical examination resourced countries and many women with cervical The physical examination is important for eliciting cancer present with untreatable late-stage disease. It is also Opportunistic detection of early cervical cancer a ‘psychodynamic event’9 and the way the client gives the only chance for surgical cure when radio- responds may give an insight into the way they feel. If the cervix looks Read more on the gynecological examination in normal and vaginal inspection with acetic acid Chapter 1 if you feel unsure about the different (VIA) is a service that is locally available, informa- procedures. An explanation should be given about tion can be given to the client so that if appropriate how the examination will be conducted, starting she can attend at her convenience (see Chapter 26 with the need to perform an abdominal examina- on how to do VIA). Intimate examinations Vaginal examination are usually consented to, but they can in themselves cause much distress especially if a woman has been Inspection of the vulva will reveal signs of irrita- in an abusive relationship. The health provider tion, inflammation, ulcers, warts or discharge. Women who who has not been sexually active or anyone who decline vaginal examinations should not be made prefers not to have this done. If digital examination to feel they have compromised their chances of is declined or not tolerated, gentle examination 69 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS with a long cotton-wool bud may be agreed upon Investigations and can give useful information. Urine, stool and pregnancy testing Initial digital examination should be with one finger to minimize discomfort so that potential Simple dipstick testing of urine, preferably on a painful areas can be better localized. If well toler- midstream specimen, should be performed. If ated, two fingers can be inserted later to aid further macroscopic hematuria is present the client needs examination. Gentle palpation of the anterior further investigation, but always check she is not vaginal wall will determine any urethral or bladder menstruating! The presence of leukocytes or nitrites base tenderness. Examination of the posterior may indicate cystitis and if the client is sympto- vaginal wall and posterior fornix will reveal any matic a course of antibiotics should be prescribed tender nodules that could indicate endometriosis. If microscopic Asking the client to contract and relax her pelvic hematuria is detected the sample should be sent for floor muscles, together with gentle digital exami- microscopy to exclude schistosomiasis, and consid- nation of the muscles, can assess pain originating in eration given to testing for tuberculosis. Bimanual examination will losis can mimic almost any disease and in endemic determine the size, position, mobility or fixation areas should not be forgotten. Microscopic hema- of the uterus, whether the uterus is tender and turia is quite common and can occur after exercise whether there are any obvious adnexal masses. Before referral for more extensive investi- gations the test should be repeated twice. Urinary Additional examinations tract cancer is extremely rare in women under 4011. Other medical causes (including sickle cell disease) Women with the following signs and symptoms would be inferred from the history.

Recently generic 400mg quibron-t free shipping, an autologous GVAX Combination with novel targeted therapies vaccine has been manufactured to stimulate T cells in situ after The addition of DLI to novel agents active in multiple myeloma purchase 400 mg quibron-t amex, 27 allogeneic HSCT for MDS/AML. Leukemia blasts were collected such as bortezomib and lenalidomide, has been performed in before HSCT, transduced, irradiated, and reinfused between days patients with residual disease after allogeneic HSCT. Two-year overall survival rates were nations are well tolerated, do not increase risk of GVHD over DLI 22,23 56% in patients who received at least one vaccination, compared alone, and result in deep remissions. The combination of with 18% in an historical control cohort. Alternatively, DLI can be 5-azacytidine followed by DLI in older patients with relapse of combined with recipient dendritic cells, either unmanipulated or AML or CML after allogeneic HSCT is feasible and induces a 66% 24 pulsed with tumor antigens, to enhance T-cell activity. Other combinations of disease-modifying agents with DLI can be ex- plored, such as sorafenib plus DLI for relapsed AML or the Immune blockade immunomodulatory agent lenalidomide plus DLI outside of the CTLA-4 blockade to inhibit this negative regulatory pathway over myeloma setting. T-cell activation has efficacy in relapsed and refractory malignan- cies, including non-Hodgkin lymphoma. Blockade with ipili- mumab, an anti-CTLA-4 antibody, during relapse after allogeneic Ex vivo activation HSCT results in increased CD4 T-cell counts and activation Activation of DLI effector cells before infusion may maximize GVL without increasing Tregs. Culture of lymphocytes with IFN- , IL-2, and anti-CD3 feasible in 29 patients without induction of significant GVHD. Allogeneic CIK cells demonstrate response rates of 30% release inhibition exerted by AML cells on minor histocompatibility in several trials of relapsed AML, sometimes with longer duration antigens-specific CD8 T cells. Blockade of this pathway may of response than was observed after the original HSCT. Hematology 2014 573 Novel approaches toward maximizing antigen specificity of DLI, not just on the DLI product, but also on identifying a risk-adapted namely expansion of naturally occurring lymphocytes directed approach to DLI to allow earlier intervention and maximize clinical toward tumor-specific antigens such as BCR-ABL, PR1, and WT1 outcomes in the setting of relapse after allogeneic HSCT, which at or genetic engineering of tumor-specific cells against CD19, CS-1, the present time entails such a poor prognosis. NY-ESO 1, CD123, WT1, and p53 are currently at the forefront of graft-versus-malignancy research, as reviewed by Drs Bollard and Disclosures Grupp in separate chapters in this publication. Conflict-of-interest disclosures: The authors declare no competing financial interests. Off-label drug use: Chemotherapy agents used Alternative donor DLI sources for transplantation. Use of unmanipulated DLI from alternative donors is also being explored. Comparison between trials of prophylactic and therapeu- Correspondence tic DLI from HLA-mismatched and haploidentical donors is compli- Edwin P. Alyea, MD, Dana-Farber Cancer Institute, 450 Brookline cated by the wide range and schema of cell doses administered, the Ave. Rates of acute GVHD References grades III-IV range from 14% to 32%. CD8( ) T-cell immunity between degree of HLA mismatching and either acute or chronic against cancer-testis antigens develops following allogeneic stem cell GVHD or efficacy are noted. Comparative efficacy versus DLI from transplantation and reveals a potential mechanism for the graft-versus- matched sources is difficult to evaluate because large, head-to-head leukemia effect. Allogeneic T-cell clones when mismatched DLIs are administered in escalating doses able to selectively destroy Philadelphia chromosome-bearing (Ph1 ) starting at 1 105 to 1 106 CD3 cells/kg. Reversal of in situ T-cell indicating that cord T cells may be a future source of DLI. Cytotoxic T lymphocytes specific Risk-adapted use of DLI for a nonpolymorphic proteinase 3 peptide preferentially inhibit chronic Cytogenetic and molecular determinants are critical factors affect- myeloid leukemia colony-forming units. Graft-versus-leukemia target factors and stage at time of HSCT comprise a disease risk index that antigens in chronic myelogenous leukemia are expressed on myeloid can be used to stratify patients for risk of relapse after HSCT and progenitor cells. Finding the sweet spot for donor lymphocyte infusions. Adoptive immuno- lymphocyte counts have been postulated. The use of prophylactic therapy evaluating escalating doses of donor leukocytes for relapse of DLI from matched-related donors when stratified for risk of relapse chronic myeloid leukemia after bone marrow transplantation: Separa- based on the presence of mixed chimerism was studied in 50 tion of graft-versus-leukemia responses from graft-versus-host disease. This approach achieved a 4-year progression-free survival of 9. Durability of responses following 65% and overall survival of 75% (60% and 61%, respectively, in donor lymphocyte infusions for patients who relapse after allogeneic very-high-risk patients with 17p deletions). Rates of severe GVHD stem cell transplantation for chronic myeloid leukemia. A risk-adapted algorithm in pediatric leukemia involving preemp- 10. Long-term follow-up of tive DLI for mixed chimerism until full donor chimerism was patients who achieved complete remission after donor leukocyte achieved demonstrated superior rates of relapse and survival versus infusions. Donor lymphocyte infusion for relapsed hematological malignancies after allogeneic hematopoietic cell transplantation: prognostic relevance of the initial CD3 T cell dose. Although responses to DLI, particularly in CML, demonstrate the 12. Prospective trial of chemotherapy potential potency of a GVL effect, a clear and effective role for DLI and donor leukocyte infusions for relapse of advanced myeloid malig- after allogeneic HSCT for other malignancies is still to be defined.