Cytogenetics

How I Treat Acute Myeloid Leukemia (for elders)

July 1, 2013 Chemotherapy, Cytogenetics, Hematology, Transplantation No comments ,

Elders With Acute Myeloid Leukemia

The management of older patients with AML is challenge. The overall survival of this population is shown in Figure 1.

Figure 1. AML in older adults (older than 60 years): overall survival.

Induction Therapy

There has been much discussion, controversy, and a lack of accurate data, given the widely disparate treatment approaches for such patients. In some studies standard intensive therapy was given for all fit older patients rather than adopting a purely palliative approach. In Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Jacob M. Rowe et al. offered all AML patients induction therapy, unless those presenting with prohibitive comorbidities.

There are several important principles in the management of such an older patient. Once the decision is made to treat, then standard doses of induction should be given. Attenuation of induction is contraindicated. A low dose will not reduce the toxicity and is more likely to lead to ineffective therapy with a similar degree of myelosuppression. Fit older adults tolerate chemotherapy at least as well as younger patients, but they do not tolerate prolonged aplasia.

Thus, the patient should receive a dose of daunorubicin of at least 60 mg/m2 for 3 days as induction. The achievement of CR (complete remission) remains of paramount clinical significance, and this is an important endpoint also in older patients, particularly when considering quality of life.

For patients older than 75 years of age, Jacob M. Rowe et al. offer standard induction therapy to any of patient who they think will tolerate intensive induction chemotherapy. The presence of comorbidities encompasses a broad spectrum, ranging from those that should be treated with supportive care only, which composes the administration of blood products and antibiotics, to therapy with hydroxyurea and escalating to low-dose cytarabine or some of the new hypomethylating agents, the farnesyltransferase inhibitors or, preferably always, a clinical trial exploring an investigational agent.

Postremission Therapy

For younger patients decision for postremission therapy should be based on cytogenetic and molecular determinants, regardless of other factors. However, for older patients, most current investigations prescribe postremission therapy, irrespective of the cytogenetics at presentation. There is enormous uncertainty and controversy regarding the optimal postremission therapy in older patients. In contrast to younger adults, the value of postremission therapy has never been unequivocally established for older patients. The available approaches for postremission consist consolidation chemotherapy and allogeneic HSCT.

It is common practice and virtually every published clinical trial for older patients with AML includes one or more courses of consolidation therapy. One study conducted a large of 1314 older patients. In this study, patients revceived standard induction therapy, and, if in remission, received the identical course of induction as their first course of consolidation therapy. Patients were then randomized to receive 3 further cycles of consolidation or only observaton. The outcomes in both groups were identical, demonstrating that there is no particular value in intensifying postremission therapy beyond a single course of consolidation. However, this study did not address whether or not any consolidation is required in older adults. This important issue remains open.

It is clear that older patients cannot tolerate the same doses of consolidation therapy that are administered to younger patients. Typically, doses are decreased for patients between 55 and 70 years of age and are further reduced for those older than 70 years of age.

The other approach is allogeneic HSCT. Older patients who do not enter on a clinical study should undergo allogeneic HSCT, if a matched sibling or matched unrelated donor exists. The reduced-intensity conditioning (RIC) conditioning regimens should be considered. The advent of RIC regimens as preparative regimens before allo-SCT may make a significant impact on the long-term survival of such patients with AML. Although there is a paucity of prospective data regarding RIC transplantations, recent studies emphasize the feasibility of this procedure, the curative potential and tolerability in older patients.

Should any consolidation be administered before RIC transplantation? Although for patients receiving standard ablative conditioning allogeneic transplantation there are data suggesting that there is no benefit for the administration of any prior consolidation in CR1, no such data exist for patients undergoing RIC tansplantation. Although a strong rationale exists for administering some form of intensification before RIC, in an attempt to minimize the leukemia burden and allow time for generation of the graft-versus-leukemia effect, in practice the design of cooperative group studies is no uniform. We offer allo-SCT to older patients after successful achievement of CR without any consolidation in order to reduce the transplantation-related toxicity.

However, for older patients with unfavorable cytogenetics, whether to offer RIC remains open. There are almost no data on RIC transplantations performed in patients with unfavorable cytogenetics because younger patients with unfavorable cytogenetics almost always undergo myeloablative conditioning.

The Management of Myelodysplastic Syndromes (MDS)

June 21, 2013 Chemotherapy, Cytogenetics, Hematology, Pharmacotherapy, Therapeutics, Transplantation 3 comments , , , ,

The myelodysplastic syndromes (MDS) are a collection of myeloid malignancies characterized by one or more peripheral blood cytopenias. MDS are diagnosed in slightly more than 10,000 people in the United States yearly, for an annual age-adjusted incidence rate of approximately 4.4 to 4.6 cases per 100,000 people. They are more common in men and whites. The syndromes may arise de novo or secondarily after treatment with chemotherapy and/or radiation therapy for other cancers or, rarely, after environmental exposures. De novo MDS is called primary MDS while the other is called secondary MDS. Indeed, the natural history of secondary MDS is expected to be worse than primary MDS. In this post we mainly focus on primary MDS and any recommendations for therapies here should be interpreted with caution when considering patients with secondary MDS.

Risk and Prognosis

There are three scoring system to evaluate the risk and prognosis of myelodysplastic syndromes (MDS) including: IPSS (International Prognostic Scoring System, 1997), WPSS (the WHO classification-based Prognostic Scoring System), and IPSS-R (Revised-IPSS, 2012).

IPSS (table 1) is the most widely used classification system for patients with MDS. 3 factors including the percentage of bone marrow myeloblasts, the diagnostic cytogenetics, and the number of cytopenias are used to generate a prognostic score. However, there are some limitations of IPSS: 1. the lack of inclusion of secondary (after prior cytotoxic therapy) MDS cases, 2. the inclusion of many patients now considered to have AML, 3. the lack of “treated” cases, and 4. the unknown impact of currently available therapies.

Table 1. The International Prognostic Scoring System (IPSS) for MDS.

Score
Prognostic variable00.51.01.52.0
Bone marrow blasts (%)< 55-1011-2021-30
Cytogenetics*GoodIntermediatePoor
Cytopenias, n0 or 12 or 3

 

ScoreIPSS subgroupMedian survival (years)
0Low5.7
0.5-1.0Int-13.5
1.5-2.0Int-21.2
> 2.5High0.4

*Good: normal, -Y, del(5q), del(20q); intermediate: other abnormalities; poor: complex (≥ 3 abnormalities) or chromosome 7 anomalies.
†Platelets < 100,000/μL; hemoglobin < 10 g/dL; neutrophils < 1,800/μL.

Reproduced from Greenberg P, et al. Blood. 1997;89:2079-88 © 1997 by The American Society of Hematology.

WPSS (table 2) makes use of the WHO subclassifications and supports the intuitive notion that the need for red cell transfusions predicts for a worse prognosis. The risk groups of WPSS are very low (0 point), low (1 point), intermediate (2 points), high (3 to 4 points), or very high (5 to 6 points). The median survival and risk of progression to AML at 5 years is 140 months/3%, 66months/14%, 48 months/33%, 26 months/54%, and 9 months/84%, respectively. Note that two categories of RAEB were recognised by the WHO classification, in which RAEB-1 and RAEB-2 with 5-9% and 10-19% blasts, respectively.

Table 2. WHO classification-based Prognostic Scoring System.

WHO classification-based Prognostic Scoring System for MDS.

In IPSS-R (table 3) bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation.

Table 3. Revised-IPSS

Compared with IPSS, the IPSS-R model showed effective separation of the IPSS patient risk categories and more effectively discriminated prognostic risk for these patients than the IPSS. Data indicated that 99% of the patients in the IPSS-R Very low and Low risk subgroups encompassed those who had been classified as IPSS Low and Intermediate-1; 81% of those in the IPSS-R High and Very high risk subgroups had been classified as IPSS Intermediate-2 and High.

The Management of MDS

After the evaluation of risk and prognosis, comes the management of MDS. Which patient should be treated and how?

Figure 1. Approach to Therapy of MDS Patients

Myelodysplasia is an incurable disease with non-transplantation therapy, but highly variable in its natural history. Treatment considerations must take into account many factors, including the pathologic diagnosis, the prognosis based on the IPSS, WPSS, or IPSS-R, the unique disease features in that particular patient, feasibility of performing a clinical trial, the appropriateness of a bone marrow transplantation, and indeed the philosophy of the patient and the family concerning his or her care.

In addition, if the patient has secondary MDS, tolerability of therapy is probably worse because of previous exposure to DNA-damaging agents and predicting how patients with secondary MDS will respond is difficult because of a lack of data and exclusion of such patients from most clinical trials.

Until now MDS remains a challenge for clinicians because of the older patient milieu, the disease heterogeneity, and the lack of effective medical therapy. And the choice between therapies is hampered by a relative lack of prospecitve randomized trials.

Firstly, what we should do after evaluation is to determine whether to treat or not. There are patients who have MDS based on sound pathologic and clinical criteria who might best be served by observation. Treatment should be reserved, and potentially the diagnosis transmitted to the patient and family, only if there are symptoms resulting from anemia or other cytopenias or perhaps presymptomatic anemia or severe thrombocytopenia.

Once the decision to treat is made, different approaches are available. However, we don’t know the standard algorithm beacuse lack of prospective randomized trials. We lack of effecive therapeuitc approach for this disease at present.

Supportive Care

Supportive care includes blood components transfusion, treatment of neutropenia and possible infections, and bone marrow stimulation.

Patients with moderate-to-severe anemia require RBC replacement. Transfusing packed RBCs for severe or symptomatic anemia benefits the patient temporarily, only for the life span of the transfused RBCs (2-4 wk). Patients with congestive heart failure may not tolerate the same degree of anemia as young patients with normal cardiac function, and slow or small-volume (eg, packed RBCs) transfusions with judicious use of diuretics should be considered.

Patients with multiple RBC transfusions might develop transfusion-induced iron overload which can incur significant damage of the liver, heart, pancreas, and other tissues. Current guidelines recommend starting iron chelation therapy in those patients who have received 20-25 units of packed RBCs or who have a serum ferritin level of >1000 μg/L. However, there are absolutely no definitive data concerning the frequency of such complications, let alone whether patient outcomes might be improved by the use of chronic iron chelation therapy. Tow iron chelation agents have been approved by FDA for the indication of iron overload: deferoxamine and deferasirox.

The notion of using hematopoietic growth factors to treat the cytopenias of patients with MDS is attractive but certainly limited by the problem of an intrinsically deranged and therefore potentially unresponsive marrow stem cell. Nonetheless, virtually every patient with MDS and anemia at some point receive an erythropoietic growth factor. However, there is incomplete information and confusion about the likelihood of response, the optimal dose, and whether to use a short- or long-acting agent. 25% of patients with anemia will respond (reduce their transfusion requirement by at least 50% or increase hemoglobin by 1g/dL) and response can take 8 weeks or more. It is common practice to increase the dose of erythropoietic growth factor once or even twice before concluding that the patient is unresponsive to single-agent erythropoietin. Patients who are not ransfusion dependent at baseline or who have relatively low intrinsic levels of serum erythropoietin (< 500 mIU/mL) are more likely to respond with response duration in 1 to 2 years. Lack of response could be the result of insufficient iron stores, but the presumptive usual problem is an intrinsically unresponsive marrow. The hemoglobin response to erythropoietin may be improved from 25% to 40% with the addition of low-dose granulocyte colony-stimulating factor.

Platelet transfusion is beneficial to stop active bleeding in thrombocytopenic patients, but the life span for transfused platelets is only 3-7 days. Routine use of platelet transfusions to support nonbleeding (even severly) thrombocytopenic patients is not advisable. The ASCO clinical guideline for prophylactic platelet transfusion also suggests that many of these patients can be observed without prophylactic transfusion, reserving platelet transfusion for episodes of hemmorrhage or during times of active treatment.

There are no useful currently available cytokines for thrombocytopenic MDS patients.

Neutropenia without a history of infection is a poor justification for initiation of therapy. Randomized studies did not demonstrate any real clinical benefit of granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. If neutropenia with infection, manage patients with board-spectrum antibotics necessary. If with systematic serious fungal infection antifungal agents should be given.

Transplantation

The HSCT is the only modality to cure this disease. But it dose not mean every patient diagnosed with MDS should be referred for such a procedure. Patients can reasonably safely be transplanted in the standard (myeloablative) conditioning regimen up to age 55 to 60 years. The outcome after transplantation for those with indolent disease is superior to that in patients with more aggressive MDS. Recent data suggest that lower risk paitents (according to the WHO or WPSS) do very well with allogeneic transplanation, whereas those with 5% to 20% marrow blasts have only a 25% to 28% 5-year overall survival.

Because of the possibility of diminishing overall life expectancy resulting from treatment-related mortality in those with good prognosis, it is recommended that allogeneic transplantation be used in low and intermediate-1 IPSS patients only after disease progression, whereas patients with more aggressive histology/prognosis should be transplanted immediately on recognition that a donor exists.

Treatment-related mortality difference between matched-sibling transplantation and matched unrelated donor transplantation is very small, as a result there is no distinction about whether there is a family donor or a unrelated donor.

For patients between 55 and 70 to 75 years of age, it is reasonable to consider a reduced-intensity conditioning (RIC) regimen. It is clear that treatment-related mortality associated with RIC is no higher than that seen with full transplantations in younger patients. However, the major problem of this approach is that we lack of long-term data with regard to disease relapse.

Another problem for transplantation, particularly for RIC, is the excess marrow myeloblasts or the relevance of disease control. It is clear that in AML patients fewer marrow blasts at the time of transplantation portend for a better outcome than if the transplantation is done in the presence of more fulminant disease. But in MDS patients the indication of chemoresponsivity or the value of pretransplantation cytoreduction is unclear. Nonetheless, the presence of more than 5% to 10% blasts in the marrow of an MDS patient probably makes transplantation, particularly with RIC, less likely to succeed. So it is therefore reasonable to administer one or 2 cycles of “MDS-induction therapy” with a DNA-hypomethylating agent in an attempt to “perform an in vivo purge” of the marrow blasts before the allogeneic procedure.

Lenalidomide

For MDS patients with “5q-” syndrome, or with 5q- cytogenetic abnormality alone without the syndrome, or 5q- with other cytogenetic abnormalities, an effective therapy has emerged. Lenalidomide produces a 67% rate of transfusion independence and major increases in the hemoglobin. Although the FDA-approved label for lenalidomide calls for dose modification if myelosuppression is noted, recent data suggest that a more aggressive dosing scheme might be considered if optimal support can be provided. The median time to response is 4.4 weeks; the median duration of the response has not yet been reached. However, the clinical trial detailing this impressive responsive rate was restricted to those with low-risk and IPSS-1 disease, platelet counts greater than 50,000, and neutrophil counts greater than 500.

But with the rationale of lenalidomide implying that major disease-modifying activity is possible because of likelihood of elimination of the karyotypically abnormal clone, lenalidomide dose appear to be a major advance for patients with 5q- chromosome abnormalities and should be used as initial therapy in such patients who require treatment.

Immunosuppressive Therapy

The patient subgroup who might benefit from immunosuppressive is difficult to define. The rationale of immunosuppressive therapy is that immune-mediated suppression of normal stem cell function, analogous to the situation in aplastic anemia, has been postulated to account for cytopenias in some MDS patients. Selected patients treated with either cyclosporine A or an antihympcyte-globulin (ATG) based regimen can experience improvements in cytopenia in about one-third to one-half of the cases. Patients who are HLA D15 positive, who tend to be younger, or who have lower platelet count irrespective of marrow cellularity are more likely to respond to such immunosuppressive manipulations. Conversely, another study suggests that hypocellularity and low IPSS score are predictors of response to immunosuppressive therapy. Of note, studies to define the optimal patients in whom such therapy is appropriate remain to be developed.

Table 4. Proposed Modified International WorkingGroup (IWG) Response Criteria for MDS

Table 5. Proposed Modified International WorkingGroup (IWG) Response Criteria for Hematologic Improvement

Cheson et al. Blood. 2006;108:419‐425.

Cheson et al. Blood. 2000;96:3671‐3674. (The old IWG response criteria)

Patients who are non 5q- and ineligible for immunosuppressive therapy and transplantation

Lenalidomide. A trial including 214 patients with non 5q- MDS were treated with lenalidomide at a starting dose of 10 mg daily (either continuously or on a cycle of 21 days on, 7 days off) were recently published. A total of 26% of these patients experienced a reduction in their transfusional needs, which is roughly comparable with what is often obtained with erythropoietin or DNA-hypomethylating agents. The median time to response was 4 weeks and the duration of response was 7 months.

However, the eligibility for this trial required low or intermediate-1 IPSS risk MDS and excluded patients with secondary MDS or those who platelet counts were less than 50,000/μL or whose neutrophil counts were less than 1000/μL.

DNA-hypomethylating agent. Clinically, those with MDS subtypes with excessive numbers of marrow myeloblasts resemble the situation in high-risk (older patient or adverse chromosome prognosis) AML. The class of drugs most useful in MDS and applicable to all subtypes are the DNA-hypomethylating agents 5-azacitidine and decitabine.

Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.

Ont clinical trial showed that an early crossover design dampened any potential survival benefit attributable to azacitidine. However, the results demonstrated a delay in time to transformation to AML in those initially randomized to the study drug. There was a much higher response rate in the experimental  arm, and an ancillary quality of life study proved that patients randomized to azacitidine fared better.

We administer 4 cycles at 75 mg/m2 subcutaneously for 7 days every 28 days, rarely make dose adjustments, and do a bone marrow after cycle 4 to determine whether additional cycles are indicated. However, for many, the decision to continue or not is relatively difficult.

How I treat acute myeloid leukemia in adults (strategies)

May 31, 2013 Chemotherapy, Cytogenetics, Hematology, Pharmacotherapy, Therapeutics, Transplantation No comments , , , , ,

More than one quarter of a million adults throughout the world are diagnosed annually with acute myeloid leukemia (AML). Few diseases other than acute myeloid leukemia (AML) engender so much personal and institutional passion regarding treatment strategies. The median age of AML is 72 years of age, as reported by the Swedish Acute Leukemia Registry, a model for collection of real world data.

Although some improvement during the last 4 decades is apparent among younger patients, still only approximately 35% of such patients entered on clinical trials are cured of their disease. However, little progress occurred among older patients and indeed only those with acute promyelocytic leukemia (APL) which is a rare subgroup enjoy the excellent outcome and likelihood of cure we all desire.

Management of AML in Adults

To some extent, the management of adults with AML appears to be standardized. However, much of the so-called conventional therapy has been established with a lack of data or without rigorous review of the existing evidence; and so, considerable uncertainty remains. Such uncertainty is reflected in the significant diversity in the management of patients with AML, both in induction of older patients and postremission therapy of all patients.

Generally, the management of AML can be divided into three parts including the induction therapy, the postremission therapy, and the hematological emergent management. The induction therapy regimen now is standarized. The choice of induction and postremission thearpy is primarily and solely determined and based on the cytogenetic and molecular determinants at diagnosis. However, possibly minimal residual disease (MRD) after induction therapy, as determined by refined molecular or immunophenotypic analyses, plays a role in deciding the choice of postremission therapy.

When a patient is newly diagnosed with AML, the first thing to do is to evaluate the cytogenetics and karyotype of the patient,since that the two is important in the determining of the risk status, the prognosis, and then the treatment strategy of AML. According to the cytogenetics and karyotype the risk status of AML can be divided into three categories consisting of better-risk (favorable), intermediate-risk, and poor-risk (unfavorable).

Table 1. Risk Status of AML Based on Cytogenetics and Molecular Abnormalities

Table 2. Standardized Reporting for Correlation of Cytogenetic and Molecular Genetic Data in AML with Clinical Data

Induction Therapy

Although in the early 1990s several randomized studies of induction therapy suggested that using idarubicin, mitoxantrone, aclarubicin, or amsacrine demonstrated superior results compared with daunorubicin, there is no evidence that these studies reflected a true biologic advantage rather than a lack of dose equivalence. So the standard induction therapy regimen remains the “3+7”. It has now been established that the traditional approved dose of daunorubicin (45 mg/mfor 3 days) is no longer appropriate as induction therapy for AML. A recent randomized trial for younger patients under age 60 years reported a significantly higher complete remission (CR) rate for patients receiving 90 mg/m2 of daunorbuicin compared with 45 mg/m2. The overall survival was also improved with the higher dose of daunorubicin.

The E1900 trial, which was undertaken by the Eastern Cooperative Oncology Group (ECOG) in 657 younger patients, compared a daunorubicin dose of 90 mg/m2 versus 45 mg/m2 in a 3+7 schedule for the first induction course. The higher dose achieved a significantly higher overall remission rate, with more patiens in CR after the first course and a better overall survival (23.7 vs 15.7 months). However, a study by Dutch-Belgian Hemato-Oncology Cooperative Group showed that with the similar approach in older patients with AML the overall remission rate was similarly improved, but overall survival was not, except in the case of patients in the 60- to 65-year subgroup.

So the induction therapy regimen is 3+7 that daunorubicin 90 mg/m2 for 3 days together with cytarabine 100 mg/m2 for 7 days.

Postremission Therapy

Once the patient get CR after induction therapy postremission therapy need consideration. The choice of postremission therapy could be allogeneic hematopoietic cell transplantation (allo-HSCT), autologous transplantation (auto-HSCT), and consolidation chemotherapy. The decision for postremission therapy should be based on cytogenetic and molecular determinants, regardless of other factors.

Allo-HCT provides the most potent antileukemic effect of any postremission strategy in AML, as demonstrated by the lowest rates of relapse in all clinical studies. The donor categories of allo-HCT consist of HLA-identical sibling donor, matched unrelated donor (MUD), genetically haploidentical donor, and umbilical cord donor. Probably the HLA-identical sibling donor is the first-line and preferred choice, because other three choices might have higher rates of mortality and morbidity associated with GVHD (graft-versus-host disease). Although there is a substantial transplantation-related mortality of 15% to 20% with allo-HCT, the reduction in the relapse rate significantly outweighs the transplantation-associated risk.

In AML patients, it is clear that fewer marrow blasts at the time of transplantation portend for a better outcome than if the transplantation is done in the presence of more fulminant disease. So to obtain CR before transplantation in AML is a rule (see post “The Management of Myelodysplastic Syndromes”). However, in relapsed AML, patients with CR1 less than 6 months have less than 20% of likelihood to achieve CR2, where we would elect to proceed to an transplantation in an untreated first relapse. But there is a expection, it is older individuals with relapsed AML, more than or equal to 60 to 65 years. In these patients a RIC often is the preferred conditioning regimen before transplantation, but the likelihood of a cure when transplantation a patient with elevated blasts with RIC is low, where our own preference in this case would be to administer one cycle of induction therapy in an attempt to obtain a better control of the disease before transplantaion.

However, not all patients with AML should undergo hematopoietic cell transplantation. Patients whose leukemia cells expressing more favorable mutations with normal karyotype at diagnosis such as mutation of NPM1 or CEBPA have a more favorable outcome and may not benefit from an allo-HCT. These patients should not undergo allo-HCT.

Table 3. Suggested indications for allo-HSCT

If there is no HLA-identical sibling donor, MUD donor, genetically haploidentical donor, or umbilical cord donor could be the alternative approach. But, a recent study showed that there was an increased replase rate in MUD transplantation for AML patients in CR1 and the leukemia-free survival was also significantly improved for patients receiving a sibling transplantation.

There was an increased relapse rate in MUD transplantations for AML patients in CR1 and the leukemia-free survival was also significantly improved for patients receiving a sibling transplantation. Although the presence of GVHD is associated with reduced relapse of AML, it dose not appear that such an effect is dependent on the degree of genetic disparity and the best donor remains the most closely matched donor.

If allo-HCT is chosen, a fully myeloablative conditioning regimen is appropriate and the reduced-intensity conditioning (RIC) regimen should be reserved for older patients or those with significant comorbidities. The transplantion should be underwent immediately after the CR1 without any consolidation chemotherapy. 2 retrospective analyses from large international registries suggest that there is no benefit to adding any consolidation therapy before an allo-HCT. Also the allo-HCT transplantation should not be delayed or reserved until the patient has a event of relapse. Delaying transplantation until after relapse is a misleading strategy.

In the majority of major prospective studies published over the past decade, a lower relapse rate was reported for patients undergoing an autologous transplantation compared with chemotherapy. If autologous transplantation is chosen, the patient should receive 2 cycles of consolidation therapy with high-dose cytarabine (3g/m2 given every 12 hours on days 1, 3, and 5) followed by the transplantation. The rationale for using an autologous transplantation is based on the fundamental concept that the optimal approach to postremission therapy is based on the regimens with the most potent antileukemic activity, provided this effect is not abrogated by unacceptably high mortality. Currently, the mortality rate associated with an autologous transplantation is less than 2%, which results from the technology that collecting hematopoietic cells from the peripheral blood. Of note, if the patient is in the poor-risk group, autologous transplantation should be avoided. I think the reason is associated the unfavorable cytogenetic mutations or karyotype.

One point must be emphasized that if the patient dosen’t achieve CR after the first induction course (i.e., the patient dosen’t clear his/her blasts in bone marrow by day 14 after the first induction therapy) but subsequently achieve CR after the second induction therapy, the prognosis is similar to those achieving CR with one cycle of induction. Thus, the postremission strategy should not be altered if the patient eventually responds successfully to the induction therapy.

Table 4. Response Criteria in AML

Blood 2009; 115: 453-574

Hematological Emergencies

Patients with initial AML may experience hyperleukocytosis which could result in leukostasis (when the WBC > 200 × 109/L) and therefore potentially lethal central nervous system and pulmonary complications. The optimal emergent management is uncertain, and one approach is to initiate immediate induction thearpy. An alternative strategy consists of daily leukapheresis with the concurrent administration of hydroxyurea at doses of 2 to 6 g/day. Generally, some experts suggest this alternative approach and wait for the initiation of induction therapy until the WBC has fallen below 40 × 109/L to 50 × 109/L, they think that this approach would increase the likelihood of achieving CR with a single cycle of chemotherapy.

The issue of prophylaxis for the central nervous system is controversial in any patients with AML and is often considered in a patient who presents initially with a high WBC. The experts don’t recommend the prophylaxis routinely if in the absence of any symptoms related to the central nervous system.

Table 5. Outcome Measures in AML

Outcome Measures in AML

Myelofibrosis (Part One)

April 23, 2013 Cytogenetics, Hematology, Pharmacotherapy, Therapeutics 1 comment , , , ,

Definition

Myelofibrosis (MF) is a clonal proliferative disease of hematopoietic stem cells, leading to an inappropriate cytokines release, fibrosis of the bone marrow, constitutive mobilization of committed progenitor cells into the peripheral blood and extramedullary hematopoiesis. MF is the most symptomatic and has the worst prognosis among the Philadelphia-chromosome-negative chronic myeloproliferative neoplasms (MPNs).

This disease may present either as idiopathic (primary myelofibrosis, PMF) or as transformation of an antecedent polycythemia vera (PV) or essential thrombocythemia (ET). PV and ET are phenotypically overlapping with PMF and manifestations and therapeutic approaches are virtually the same in PMF and PV/ET.

Myleofibrosis is characterized by a progressive clinical course. Established prognostic factors including age, hemoglobin level, and white blood cell count have been used for risk assessment, but these characteristics do not fully explain the risk of death or major clinical events.

Morbidity and mortality of myelofibrosis are usually the result of leukemic transformation, spleno-portal hypertension, and infections, as well as thrombosis and hemorrhage.

Table 1 Poor Prognosis Factors – International Working Group-derived International Prognostic Scoring System (IPSS)

Poor Prognosis Risk Factors
1Age > 65 yrs
2Presence of constitutional Symptoms
3Anemia (Hemoglobin < 10 g/dL)
4Leukocytosis (White blood cell count > 25 x 103/mm3)
5Circulating blast cells of 1% or greater

The presence of the factors in the table above defines risk degree of myelofibrosis:

  • No risk factors – low-risk
  • One risk factor – intermediate-1-risk
  • Two risk factors – intermediate-2-risk
  • Three or more risk factors – high-risk

What must be paied attention is that this system (IPSS) is used for risk evaluating from time of diagnosis. There is another assessment criteria called Dynamic IPSS plus (DIPSS-Plus) which can be used for risk evaluating at any time during the disease course. The DIPSS-Plus has three additional independent risk factors including red cell transfusion need, platelet count < 100 × 109/L, and unfavorable karyotype. The unfavorable karyotype includes complex karyotype or sole or 2 abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement.

Note that leukocytosis can happen in patients after splenectomy due to “myeloproliferative” reaction and it does not necessarily imply disease progression.

Figure 1 The Dynamic International Prognostic Scoring System (DIPSS) plus prognostic model for primary myelofibrosis (PMF).

  • No risk factors – low risk
  • 1 risk factor – intermediate 1
  • 2 or 3 risk factors – intermediate 2
  • ≥ 3 risk factors – high

These four risk groups are with respective median survivals of 15.4, 6.5, 2.9, and 1.3 years. Leukemic transformation was predicted by the presence of unfavorable karyotype or platelet count < 100 × 109/L.

Clinical Manifestations

Symptomatic myelofibrosis can present with anemia, significant splenomegaly, aberrant production of proinflammatory cytokines (which causes constitutional symptoms such as weight loss, night sweats, fever of unknow origin), severe fatigue, cachexia, and pruritis.

These manifestations include anemia (either moderate or transfusion dependent), splenomegaly and/or hepatomegaly, the development of foci of nonhepatosplenic hematopoiesis, myeloproliferation manifesting with marked leukocytosis or thrombocytosis. and increased risk of thrombohemorrhagic complications, and a spectrum of debilitating constitutional symptoms.

Biology

JAK2V617F (Janus kinase 2 mutation V617F) mutation plays an important role in the pathogenesis of myelofibrosis. JAK2V617F has been identified in approxmiately 60% of patients with myelofibrosis (half of patients with PMF and post-ET myelofibrosis and in nearly all of those with a secondary form following a previous PV). Despite its crucial role in pathogenetic role, the clinical relevance of JAK2V617F in myelofibrosis is not completely understood. In a large retrospective survey showed that JAK2V617F mutation plays a significant and independent influence on the disease phenotype and showed that many clinical manifestations are correlated with the expansion of clonal hematopoietic cells harboring the JAK2V617F mutant allele.

Management of Myelofibrosis

The treatment of MF is guided by risk stratification and the patient’s clinical needs. As we mentioned before, the risk stratification are:

  • No risk factors – low risk
  • 1 risk factor – intermediate 1
  • 2 or 3 risk factors – intermediate 2
  • ≥ 3 risk factors – high

For low- or intermediate 1-risk disease, the respective median survival of patients exceeds 15 and 6 years and even longer for patients younger than age 65 years. Therefore, the risk of allo-SCT-associated mortality and morbidity is not justified in such patients, and it is also not prudent to subject them to investigational drug therapy, considering the limited information about long-term safety of new therapeutic agents. Similarly, there is no evidence to support the value of conventional drug therapy in asymptomatic patients with low- or intermediate 1-risk diseases. For this group of patients without symptoms, “watch and wait” is preferred.

For this group of patients with symptoms, they may occasionally experience splenomegaly, nonhepatosplenic extramedullary hematopoiesis, extramedullary hematopoiesis (EMH)-associated pulmonary hypertension, fatigue, bone (extremity) pain, pruritus, or thrombocytosis with a thrombosis history. Intermediate 1-risk patients might in addition display symptomatic anemia, marked leukocytosis, or constitutional symptoms such as drenching night sweats, fever, or weight loss (cachexia). If clinical needed, it is reasonable to start with conventional drug therapy.

However, if the patient is del(5q) present, lenalidomide is the recommended first-line therapy because significant improvement.

Figure 2 Risk-adapted therapy in primary myelofibrosis.

For patients with high- or intermediate 2-risk disease can be managed by conventional drug therapy, splenectomy, radiotherapy, allo-SCT, or experimental drug therapy. With each one of these treatment modalities except allo-SCT, the primary goal is palliation of anemia, symptomatic splenomegaly, constitutional symptoms, or disease complications from EMH (extramedullary hematopoiesis).

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Drug Targets and Cell Signaling Pathways

February 18, 2013 Cytogenetics, Pharmacology No comments , ,

There are cell signaling pathways and they are Erb pathway, VEGF pathway, PARP pathway, IGF-1 pathway, Hedgehog (Hh) pathway, and Ubiquitin-Proteosome pathway.

Erb pathway

There are four types of Erb receptors including EGFr (ErbB1), HER2/neu (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Ligands of these receptors bind to Erb receptors, then dimerization happens, finally the tyrosine kinase of receptors are activated, which results in first increased tumor proliferation, angiogenesis, growth, and metastases potential; and second decreased apoptosis.

VEGF pathway

VEGF family includes VEGFR-1, VEGFR-2, and VEGFR-3. VEGF pathway is activated and cell signal is transmitted, as a results increased angiogenesis, lymphangiogenesis happens.

PARP pathway

PARP is involved in the DNA repair after DNA damage due to radiation therapy, chemotherapy and so on. PARP inhibitors can prevent the DNA repair after DNA damage, which results in persistent DNA damage and finally the apoptosis 0r cancer cell death.

IGF-1 pathway

IGF-1 pathway provides a potent proliferative signaling that stimulates growth in many different cell types and blocks apoptosis including cancer cells.

Hedgehog (Hh) pathway

Hh pathway is relative to cell proliferation, survival, and angiogenesis.

Ubiquitin-Proteosome pathway

This path is involved in the ubiquitination and proteasomal degradation of CRL substrates, which is important for normal cell cycle regulation and DNA replication related to cancer cell growth.