Transplantation

The Management of Therapy-related Acute Meyloid Leukemia

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

Until recently, the term “secondary leukemia” broadly included any AML with a history of prior malignancy as well as patients with any antecedent hematologic disorder and, in some series, any patient who presented with unfavorable cytogenetics.

Among therapy-related AML patients, 70% present with abnormalities of chromosome 5 or 7, which is the most typical presentation after the exposure to alkylating agents and/or ionizing radiation; 30% are those that arise after treatment with topoisomerase-2 inhibitors.

In general, the management of therapy-related AML is fraught with uncertainty because, among other reasons, most early studies included small numbers of patients and were retrospective. There have been no prospective randomized studies specifically directed at the treatment of therapy-related leukemias. Furthermore, the published data often included patients with myelodysplastic syndromes.

Induction Therapy

Hisytorically, it was presumed that every patient with therapy-related leukemia had an adverse prognosis and that standard induction therapy was inappropriated. However, there is no evidence that any induction therapy is superior to the standard 3+7 regimen. Among young adults, quite remarkably, prospective studies report an almost identical CR rate of 55% to 60% for patients treated with recognized unfavorable cytogenetics, and there are no reports that anything is better than this. Standard induction should remain the induction therapy regimen.

Postremission Therapy

Figure 1 AML in Patients Less Than 60 Years of Age.

It is still somewhat controversial whether thearpy-related AML has a prognosis that is intrinsically worse that de novo AML, independent of cytogenetics. In a very large database, the National Cancer Research Institute in Great Britain reported a significantly worse outcome for therapy-related AML than de novo AML, within each cytogenetic risk group (favourable, intermediate, and adverse). But, still, the management of patients with therapy-related AML should be guided by the cytogenetic and molecular features, which is the same as de novo AML.

Although there is a perception that any patient with therapy-related AML should be considered at high risk and referred to an allogeneic transplantation, there is no evidence that the long-term outcome for patients who present with a favorable karotype, with no adverse molecular features, is different from patients with the de novo AML. Thus, such patients with favorable category should not be referred to an allogeneic transplantation in CR1.

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.

Anti-infection Prophylaxis in Cancer Patients With Neutropenia (Risk Evaluating and Patient Selection)

June 26, 2013 Chemotherapy, Hematology, Infectious Diseases, Transplantation No comments , ,

Cancer patients, particularly those with hematologic malignancies, usually have neutropenia, both disease-related and treatment-related, which makes those patients in danger of various types of infection. The way to prevent these patients from infection is prophylactic antibiotics uses. In this post we talk about how to manage neutropenia patients with cancer who are afebrile.

This post is based on the guideline of ASCO.

Assessing the risk of developing an FNE (febrile neutropenic episode)

Evidence data for the evaluation of outpatients is not available, therefore the ASCO Panel considered evidence from studies on inpatients or mixed populations.

Risk for developing an FNE should be systematically assessed (in consultation with infectious disease specialists as needed), including patient-, cancer-, and treatment-related factors.

Risk factors for FNE or for complications resulting form an FNE in oncology patients undergoing systemic chemotherapy are list in Table 1. These risk facors are grouped by characteristics of: patients and their health status, their underlying malignancy, and the chemotherapy regimen they are receiving. Studies cited in Table 1 and others have developed and tested models to predict likelihood of an FNE in the first or a subsequent chemotherapy cycle. On the basis of members’ expert opinion, the Panel recommends that patients starting a new chemotherapy regimen undergo an individualized but systematic assessment of risk for an FNE to evaluate the factors list in Table 1, involving consultation with local infectious disease experts as needed.

Table 1. Factors to Consider in Assessing Risk of and FNE in Patients Unergoing Cytotoxic Chemotherapy for Malignancy.

These risk factors in Table 1 are based on patient, cancer, and treatment modality.

Antibacterial Prophylaxis

Generally, the Panel suggests that clinicaians consider the use of antibacterial prophylaxis only for patients expected to experience profound neutropenia (defined as ANC < 100/μL) likely to last for ≥ 7 days. The Panel does not recommend routine antibacterial prophylaxis for patients with neutropenia that is less severe or of shorter duration. However, prophylaxis might be recommended for patients at high risk of mortality if an FNE occurs.

The literature serach found that antibacterial prophylaxis decreased mortality when compared with pooled controls receiving either placebo or no treatment. However, in these RCTs a majority of patients were undergoing either remission induction (or reinduction) for hematologic malignancy (mostly acute leukemia) or hematopoietic SCT (HSCT). In this population group their rates of febrile episodes, clinically documented infection, microbiologically documented infection, and bacteremia are high. Thus these patients were at high risk for FNE (febrile neutropenic episode).

Few RCTs of antibacterial prophylaxis focused on patients with cancer and neutropenia at low risk for an FNE or infection. In some studies about patients with solid tumors or lymphoma, the prophylaxis significantly decreased documented febrile episodes (core temperature > 38℃) attributed to infection in the first cycle and over the full course of chemotherapy. Also prolhylaxis also significant decreased rates of probable infection and hospitalization for infection, both in the first cycle and over the full course of chemotherapy. However, it did not yield a statistically significant decrease in rates of severe infection (infection-related sepsis syndrome, death, or both) or infection-related mortality.

A subset analysis in one meta-analysis pooled data from the RCT for patients with solid tumor or lymphoma reported a statistically significant decrease in all-cause mortality during the first month of chemotherapy. However, the absolute difference in 30-day mortality was modest and the prophylaxis did not significantly decrease all-cause mortality by the end of follow-up. These data suggest that it is not recommended to routinely use prophylactic antibacterial therapy in low-risk patients.

Thus, we recommend that clinicians limit use of antibacterial prophylaxis to patients at high risk for an FNE associated with prolonged severe neutropenia (ANC < 500/µL). The risk for FNE or infection are importantly determined by the expected duration and depth of neutropenia, and other factors in Table 1. However, because direct evidence is lacking, it is difficult to define risk thresholds for the two important variables above. Thus, ASCO Panel recommend that unless one or more other high-risk features of Table 1 are present, antibacterial prophylaxis should be limited to patients expected to have profound neutropenia (ANC < 100/µL) for at least 7 days.

Antifungal Prophylaxis

For the fungal infection, three meta-analyses reported that when compared with controls, systemic antifungal prophylaxis significantly decreased mortality attributed to fungal infections. Also the need for subsequent full-dose parenteral antifungal therapy was decreased and the incidence of systemic, invasive, and/or superficial fungal infections decreased too. Again, however, most patients randomly assigned in these RCTs were at high risk for IFI (invasive fungal infection) resulting from HSCT, induction chemotherapy for acute leukemia, or other treatments that caused lengthy durations of profound neutropenia.

The most recent review pooled data from 33 RCTs found a statistically significant decrease in fungal infection-related mortality and all-cause mortality at the end of follow-up. However, metaregression analysis showed statistically significant associations between the proportion of randomly assigned patients being treated for leukemia with the treatment effects of systemic antifungal prophylaxis in both overall mortality and risk for IFI.

Data from the most recent meta-analysis of RCTs of antifungal prophylaxis also showed that pooled IFI rates (either candidiasis or aspergillosis) among controls were approximately 6% across 24 studies of patients undergoing treatment for acute leukemia and > 10% across four studies of patients undergoing HSCT, each associated with lengthy duration of profound neutropenia. Thus, the ASCO Panel recommends limiting antifungal prophylaxis to patients at substantial risk for IFI (> 6% to 10%), which is profound neutropenia (ANC < 100//µL) for at least 7 days.

                                                                                                                                               Table 2. Risk Factors for Invasive Mold Infection

Risk Factors for IFI
  • Prolonged profound peutropenia (ANC < 100/µL for > 7 days) in the context of intensive remission-induction or reinduction therapy for acute leukemia in environments where the risk for invasive aspergillosis exceeds 6%
  • Prolonged (> 21 days) severe neutropenia (ANC < 500/µL), lymphocytopenia (ALC < 500/µL), or monocytopenia (AMC < 150/µL) among allogeneic HSCT recipients experiencing graft failure
  • Use of purine analogs (eg, fludarabine) to treat malignancy for pre-HSCT conditioning
  • Use of intensive immunosuppression for treating GVHD
  • Reactivation of cytomegalovirus
  • Iron overload states
  • A previous documented invasive mold infection
  • Environmental exposures associated with personal habits, outside activities, or indoor activities
Of note: many of these risk factors may interact to enhance the risk for mold infection.

Prophylaxis for Pneumocystis jirovecii Infection

Patients receiving chemotherapy regimens associated with a risk > 3.5% for pneumonia resulting from Pneumocystis jirovecii (PCP; eg, those with ≥ 20 mg of prednisone equivalents daily for ≥ 1 month or those based on purine analogs) are eligible for prophylaxis.

Retrospective analyses suggest those at greatest risk are patients undergoing intensive induction (or salvage reinduction) for acute leukemia, allogeneic bone marrow transplantation (particularly if receiving alemtuzumab), or treatment with either high-dose corticosteroids (eg, ≥ 20 mg of prednisone equivalents daily for ≥ 1 month) or purine analogs that deplete T cells such as fludarabine or cladribine. Additionally, a recent report suggests the regimen combining rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone every 2 weeks (R-CHOP-14) is associated with elevated risk for PCP (10% to 15%), although the regimen with the same drugs every 3 week (classical R-CHOP) is not. Another recent retrospective analysis suggests that CD4+ lymphocyte counts ≤ 200/µL predicted a higher risk (approximately 19%) for PCP in patients treated for B-cell non-Hodgkin lymphoma.

Prophylaxis for Reactivation of Hepatitis B Virus (HBV) Infection

Antiviral prophylaxis should be offered to patients know to be at substantial risk for reactivation of hepatitis B virus (HBV) infection.

Reactivation of HBV infection after treatment for malignancy has been reviewed extensively. Guidelines from several other organizations suggest that patients at risk for HBV reactivaton should be screened for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B core antigen (anti-HBc). Howver, ASCO Panel concluded that available evidence was insufficient to determine the net benefits and harms of routine screening for chronic HBV infection in all individuals with cancer about to receive (or already receiving) cytotoxic or immunosuppressive therapy. The Panel recommended a more targeted approach to HBV testing, using clinical judgment to select patients at risk who are about to receive or already receiving highly immunosuppressive treatments including, but not limited to, HSCT and regimens that include rituximab.

Three groups with a history of prior exposure to HBV are at risk: patients with chronic infection and viremia, chronic inactive carriers (positive for HBsAg for ≥ 6 months but with serum HBV DNA < 2,000 IU/mL and normal serum levels of hepatic transaminases), and those with immunity against HBV because of past exposure. Factors that may increase reactivation risk include male sex, younger age, hepatic transaminase levels > the normal range or HBV DNA > 3 × 105 copies/mL before cytotoxic therapy begins, dose-intense chemotherapy, and severe immunosuppression.

Prophylaxis for HSV and VZV

Evidence summarized in some revies suggests that most HSV (herpes simplex virus) or VZV (Varicella-Zoster virus) infections in patients undergoing treatment for malignancy are the result of reactivation of latent virus from prior exposure; new primary infections are uncommon.

In the absence of HSV prophylaxis, reactivation has been reported in 37% to 57% of patients undergoing intensive chemotherapy for hematologic malignancies and in 68% to 90% of those undergoing myeloablative allogeneic HSCT.

Reactivation of latent VZV, present in most adults, results in herpes zoster; complications may include postherpetic neuralgia, zoster ophthalmicus, scarring, or bacterial superinfection. Among patients with hematologic malignancies, VZV reactivaton is reportedly uncommon after imatinib for chronic myeloid leukemia (2.6%) but more frequent after fludarabine or alemtuzumab for chronic lymphocytic leukemia (10% to 15%), treatment for Hodgkin lymphoma or autologous HSCT (25%), and bortezomib for multiple myeloma (11% to 15%). VZV reactivation occurs in 30% to 60% of those who undergo allogeneic HSCT but is typically delayed until after engraftment. The median time to reactivation among such patients has been reported to be approximately 8 months, and approximately one in five may develop postherpetic neuralgia.

It is recommended that HSV or/and VZV seropositive patients undergoing therapy for certain hematologic mailignancies should be given prophylais to prevent reactivation of infection because of HSV.

Prophylaxis for Influenza

Seasonal influenza immunization is recommended for all patients undergoing treatment for malignancy and for all family and household contacts.

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.

The Management of Acquired Aplastic Anemia (Strategies)

June 6, 2013 Hematology, Pharmacotherapy, Therapeutics, Transplantation No comments , ,

Aplastic anemia is a disease in which the bone marrow, and the blood stem cells that reside there, are damaged. This causes a deficiency of all three blood cell types (pancytopenia): red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia).

Until the 1970s, severe aplastic anemia (SAA) was almost uniformly fata, but in the early 21st century most patients can be effectively treated and can expect long-term survival.

Pathophysiology

The pathophysiology responsible for marrow cell destruction and peripheral blood pancytopenia has itself been inferred from the results of treatment in humans, with substantial in vitro and animal model support.

The success of HSCT in restoring hematopoiesis in SAA patients implicated a deficiency of HSCs. Hematologic improvement after immunosuppressive therapy (IST) implicated the immune system in destruction of marrow stem and progenitor cells.

Genetics influences both the immune response and its effects on the hematopoietic compartment. There are histocompatibility gene associations with SAA, and some cytokine genes may be more readily activated in patients because of differences in their regulation, as suggested by polymorphisms in promoter regions.

An inability to repair telomeres and to maintain the marrow’s regenerative capacity, resulting from mutations in the complex of genes responsible for telomere elongation, has been linked to patients with familial or apparently acquired SAA, with or without the typical physical stigmata of constitutional aplastic anemia.

Approximately 5% to 10% of patients with SAA have a preceding seronegative hepatitis. However, most patients do not have a history of identifiable chemical, infectious, or medical drug exposure before onset of pancytopenia.

The antigen(s) inciting the aberrant immune response have not been identified in SAA. Furthermore, the current simple mechanistic outline may be supplemented in the future with better understanding of now theoretical possibilities, suggested by provocative murine models.

Management of Acquired Aplastic Anemia

Table 1. Criteria for SAA

For patients with moderate aplastic anemia, as defined by lack of blood count criteria for SAA, observation is often appropriate, especially when they do not require transfusion support. The criteria for SAA is in Table 1. Many of these patients may have stable blood counts for years, but in some pancytopenia worsens over time.

Once the disease progresses and the patients meets the criteria for SAA or become transfusion-dependent, treatment is always required. The therapeutic strategies for SAA include immediate supportive care, transplantation (HSCT), and immunosuppressive thearpy (IST), in which HSCT and IST are called definitive treatment.

Supportive care initiates and the definitive treatment should be started as soon as possible, since prolonged delay until initiation of primary treatment for SAA is not generally desirable and can result in serious complications before definitive therapy. Watchful waiting, especially if neutropenia is profound, can be harmful and is not appropriate once a diagnosis of SAA is confirmed. To realize this goal, it is prudent to rapidly assess whether matched sibling donors exist in the family for any patients younger than 40 years of age. Why the upper limit of age is 40 years is related to the risk of GVHD and we will discuss further below.

Immediate Supportive Care

Symptoms related to anemia and thrombocytopenia can be readily corrected with transfusions. Broad spectrum parenteral antibiotics are indicated when fever or documented infection occurs in the presence of severe neutropenia (< 0.5 × 109/L). As we have discussed in the blog “Platelet transfusion for patients with cancer (part two)“, prophylatic platelet transfusion is necessary when needed, and the threshold in these patients is 10 × 109/L.

Of note, transfusion of red cells aims to alleviate symptoms of anemia, not simply to target a specific hemoglobin threshold. Adequate red blood cell transfusions in symptomatic patients should not be deferred because of fear of iron accumulation or to reduce the risk of alloimmunization. However, in some guidelines it is recommended that 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 (see post “The Management of Myelodysplastic Syndromes“).

In evaluating febrile neutropenic patients, simple chest X-ray is of limited value, so routine CT imaging of the sinus and chest is a preferred approach which followed by nasal endoscopy, bronchoscopy, and biospy for microbiologic confirmation when indicated. If fungal infection is suspected or neutropenic fever persists for more than several days despite broad-spectrum antimicrobials, empiric antifungal therapy should include drugs active against Aspergillus sp, as this pathogen has remained the most common fungal isolate in SAA patients for the past 20 years.

supportive measures alone, growth factors, androgens, or cyclosporine (CsA) are not definitive therapies. Patients should not be subject to initial trials of G-CSF or erythropoietin. Corticosteroids are of unproven benefit and inferior in efficacy to conventional immunosuppression regimens, but they are more toxic and should not be used as therapy in SAA. It is very unfortunate when a patient with SAA presents for transplant or IST but already has life-threatening fungal infection because of weeks or months of exposure to corticosteroids.

Figure 1. Algorithm for Initial Management of SAA

Algorithm for initial management of SAA

Transplantation

For malignancies, GVHD may offer graft-versus-tumor-benefits. For example, in AML the presence of GVHD is associated with reduced relapse of AML. However, in SAA GVHD is unequivocally to be avoided since the presence of GVHD in SAA definitely decreases survival and long-term quality of life.

The age of the patient with SAA is a crucial element for the decision to transplantaton. Generally, patient older than 40 years of age are not recommended to undergo transplantation since the correlation of increasing age with the increased risk of GVHD and therefore the significant morbidity and mortality of this complication is apparent. A study of more than 1300 SAA patients who were transplanted from 1991 to 2004 showed that survival at 5 years for patients younger than 20 years of age was 82%, for those 20 to 40 years of age 72%, and for those older than 50 years of age closer to 50%. Rates of GVHD increased with age, accounting for much of the decreased survival in older patients and the long-term morbidity.

The stem cell could be collected from either bone marrow or peripheral. The stem cell source also is important for survival and long-term quality of life. In a retrospective analysis, the rate of chronic GVHD was greater with peripheral blood (27%) compared with bone marrow stem cell grafts (12%) in patients younger than 20 years of age. In a subsequent retrospective analysis, similar higher rates of chronic GVHD were observed for patients of all ages undergoing HSCT with peripheral blood compared with bone marrow derived stem cell grafts.

For unrelated donor transplants, bone marrow source of stem cells was associated with lower rates of acute GVHD (31%) compared with peripheral blood-derived CD34+ cells (48%), which not only means bone marrow source is preferred than peripheral blood source but also matched sibling donor is preferred than unrelated donor.

The donor for HSCT consists of matched sibling donor and alternative donor. Again matched sibling donor is preferred since experience from larger cohorts reported in the last 5 years from the United States, Japan, Korea, and Europe suggests that the outcome with unrelated donor HSCT is still not as favorable as that of a matched sibling donor. Meanwhile, practically, identification of a matched unrelated donor and coordination with a transplant center usually takes several months, and delaying definitive IST while conducting a serach for nonfamily donor may be dangerous.

Prospective trials using umbilical cord HSCT in SAA are limited to smaller case series, which do show encouraging results. However, experience from larger cohorts in retrospective analyses indicate that overall survival is not as favorable as in pilots, at approximately 40% at 2 to 3 years. Graft rejection and poor immune reconstitution continue limit the success of umbilical cord HSCT.

Immunosuppressive Therapy

For patients older than 40 years of age, or yonger than 40 years of age but without matched sibling donor, IST is the first alternative therapeutic approach other than unrelated donor HSCT.

For patient older than 40 years of age, if initial IST fails (no response at 6 months, we define refractory SAA as blood counts still fulfilling criteria for severe pancytopenia 6 months after initiation of IST), we consider matched sibling HSCT first if he/she has a matched sibling donor. For patients younder than 40 years of age but without matched sibling donor, if initial IST fails, we conisider matched unrelated donor HSCT first if he has a histocompatible donor.

Whereas if the patient has no histocompatible donor or don’t suitable for HSCT we consider to repeat the IST therapy with rabbit ATG and CsA or with Alemtuzumab alone. If the patient remains no response 6 months after the second IST therapy, we consider HSCT (mismatched unrelated, haploidentical, or umbilical cord) or non-HSCT approach (see in Figure 1).

Standard initial IST is horse ATG (anti-thymocyte globulin) and CsA (cyclosporine), which produces hematologic recovery in 60% to 70% of cases and excellent long-term survival among responders, as shown in several large prospective studies in the United States, Europe, and Japan.

The mechanism of action by which polyclonal antilymphocyte preparations suppress immune responses is not fully understood. Possible mechanisms by which Thymoglobulin may induce immunosuppression in vivo include: T-cell clearance from the circulation and modulation of T-cell activation, homing, and cytotoxic activities. Thymoglobulin includes antibodies against T-cell markers such as CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, HLA-DR, HLA Class I heavy chains, and ß2 micro-globulin. In vitro, thymoglobulin (concentrations >0.1 mg/mL) mediates T-cell suppressive effects via inhibition of proliferative responses to several mitogens. In patients, T-cell depletion is usually observed within a day from initiating Thymoglobulin therapy. Thymoglobulin has not been shown to be effective for treating antibody (humoral) mediated rejections.

Study showed the addition of CsA to ATG increased the hematologic response rate, however, other agents such as mycophenolate mofetil, growth factors, or sirolimus to horse ATG/CsA did not improve rates of response, relapse, or clonal evolution. A more lymphocytotoxic agent rabbit ATG, has been successful in salvaging patients with refractory or relapsed SAA after initial horse ATG. But in recent large, randomized controlled study, hematologic response to rabbit ATG (37%) was about half that observed with standard horse ATG (68%), with inferior survival noted in the rabbit ATG arm. Therefore horse ATG remains the most effective regimen for first-line IST therapy regimen of SAA.

Therapy Response Evaluation

We use simple definition for hematologic response: no longer meeting blood count criteria for SAA, which closely correlates with transfusion independence and long-term survival. Hematologic improvement is not to be expected for 2 to 3 months after ATG. The majority of response (90%) occur within the first 3 months, with fewer patients responding between 3 and 6 months or after.

After ATG therapy patients with SAA needed to long-term follow-up, we will discuss this scope in another post. Coming soon.