Chemotherapy

The Management of Multiple Myeloma in Younger Patients

September 19, 2013 Chemotherapy, Cytogenetics, Hematology, Therapeutics, Transplantation No comments , , , , , , , , , ,

Therapy for multiple myeloma (MM) has advanced with gratifying speed over the past 5 to 7 years and with this progress, a degree of uncertainty has arisen about optimal approaches to therapy, particularly in the newly diagnosed patients. Indeed, using mordern therapeutic strategies, living with MM for a decade or longer has now become a reality for a significant proportion of patients.

Pathophysiology

MM is characterized by neoplastic proliferation of plasma cells involving more than 10% of the bone marrow. Increasing evidence suggests that the bone marrow microenvironment of tumor cells plays a pivotal role in the pathogenesis of myelomas.

The malignant cells of MM, plasma cells, and plasmacytoid lymphocytes are the most mature cells of B-lymphocytes. B-cell maturation is associated with a programmed rearrangement of DNA sequences in the process of encoding the structure of mature immunoglobulins. It is characterized by overproduction of monoclonal immunoglobulin G (IgG), immunoglobulin A (IgA), and/or light chains, which may be identified with serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP).

The role of cytokines in the pathogenesis of MM is an important area of research. Interleukin (IL)–6 is also an important factor promoting the in vitro growth of myeloma cells. Other cytokines are tumor necrosis factor and IL-1b.

The pathophysiologic basis for the clinical sequelae of MM involves the skeletal, hematologic, renal, and nervous systems, as well as general processes.

Development Progresses

Skeletal processes

Plasma-cell proliferation causes extensive skeletal destruction with osteolytic lesions, anemia, and hypercalcemia. Mechanisms for hypercalcemia include bony involvement and, possibly, humoral mechanisms. Isolated plasmacytomas (which affect 2-10% of patients) lead to hypercalcemia through production of the osteoclast-activating factor.

Destruction of bone and its replacement by tumor may lead to pain, spinal cord compression, and pathologic fracture. The mechanism of spinal cord compression symptoms may be the development of an epidural mass with compression, a compression fracture of a vertebral body destroyed by multiple myeloma, or, rarely, an extradural mass. With pathologic fracture, bony involvement is typically lytic in nature.

Hematologic processes

Bone marrow infiltration by plasma cells results in neutropeniaanemia, andthrombocytopenia. In terms of bleeding, M components may interact specifically with clotting factors, leading to defective aggregation.

Renal processes

The most common mechanisms of renal injury in MM are direct tubular injury, amyloidosis, or involvement by plasmacytoma.[14, 15] Renal conditions that may be observed include hypercalcemic nephropathy, hyperuricemia due to renal infiltration of plasma cells resulting in myeloma, light-chain nephropathy,amyloidosis, and glomerulosclerosis.

Neurologic processes

The nervous system may be involved as a result of radiculopathy and/or cord compression due to nerve compression and skeletal destruction (amyloid infiltration of nerves).

General processes

General pathophysiologic processes include hyperviscosity syndrome. This syndrome is infrequent in MM and occurs with IgG1, IgG3, or IgA. MM may involve sludging in the capillaries, which results in purpura, retinal hemorrhage, papilledema, coronary ischemia, or central nervous system (CNS) symptoms (eg, confusion, vertigo, seizure). Cryoglobulinemia causes Raynaud phenomenon, thrombosis, and gangrene in the extremities.

Workup

Some tests can afford important prognostic information and the subtypes of myeloma. These tests include classic CRAB measurements (calcium level, renal function, amemia, bone damage) , β2-microglobulin, albumin, lactate dehydrogenase (LDH), serum and urine monoclonal protein (24-hour) such as serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE), 24 h urine protein electrophoresis (UPEP), urine immunofixation electrophoresis (UIFE), and so on, serum-free light chain assay.

Bone marrow examinations such as morphology, FISH (fluorescent in situ hybridization) analysis of key genetic events, metaphase cytogenetics are also mandatory at present.

Table 1. Genetic Tests to Be Performed in Myeloma Patients at Diagnosis.

With these tests, multiple myeloma can be divided into three subtypes, which are solitary plasmacytoma, smoldering myeloma (asymptomatic myeloma) and active myeloma (symptomatic myeloma).

Subtypes of Multiple Myeloma

According to the latest NCCN guideline MM can be categorized into three subgroups including solitary plasmacytoma, smoldering myeloma (asymptomatic), and active myeloma (symptomatic).

Solitary plasmacytoma

Solitary plasmacytoma is a large solitary focus of plasma cell proliferation. To simplify, solitary plasmacytomas can be divided into 2 groups according to location: Plasmacytoma of the skeletal system (SBP) or Extramedullary plasmacytoma (EMP). Similarly, the latest NCCN guideline for MM categorizes solitary plasmacytoma into solitary osseous or solitary extraosseous.

Criteria for identifying solitary bone plasmacytoma (SBP) vary among authors. Some include patients with more than one lesion and elevated levels of myeloma protein and exclude patients whose disease progressed within 2 years or whose abnormal protein persisted after radiotherapy. With the use of magnetic resonance imaging (MRI), flow cytometry, and polymerase chain reaction (PCR), the currently accepted criteria are as follows:

  • Single area of bone destruction due to clonal plasma cells
  • Bone marrow plasma cell infiltration not exceeding 5% of all nucleated cells
  • Absence of osteolytic bone lesions or other tissue involvement (no evidence of myeloma)
  • Absence of anemia, hypercalcemia, or renal impairment attributable to myeloma
  • Low, if present, concentrations of serum or urine monoclonal protein
  • Preserved levels of uninvolved immunoglobulins

Diagnostic criteria for extramedullary plasmacytoma (EMP) are as follows:

  • Tissue biopsy showing monoclonal plasma cell histology
  • Bone marrow plasma cell infiltration not exceeding 5% of all nucleated cells
  • Absence of osteolytic bone lesions or other tissue involvement (no evidence of myeloma)
  • Absence of hypercalcemia or renal failure
  • Low serum M protein concentration, if present

Smoldering myeloma

Smoldering myeloma describes a stage of disease of MM with no symptoms and no related organ or tissue impairment. According to the latest version of NCCN guideline for MM, criteria for the definition of smoldering myeloma are as follows:

  • M-protein in serum ≥30 g/L and/or
  • Bone marrow clonal plasma cells ≥10%
  • No related organ or tissue impairment (no end organ damage, including bone lesions) or symptoms.

Note that the M-protein refers to the monoclonal protein produced by MM cells.

Active/symptomatic myeloma

Criteria for the definition of active/symptomatic myeloma requires one or more of the following:

  • Calcium elevation (>11.5 mg/dL) [>2.65 mmol/L]
  • Renal insufficiency (creatinine >2 mg/dL) [177 µmol/L or more]
  • Anemia (hemoglobin <10 g/dL or 2 g/dL < normal)
  • Bone disease (lytic or osteopenic)

In the section of management of MM we will discuss the specific therapeutic approaches for these three subtypes of MM.

Prognosis and Genetics

Several factors can afford important prognostic information for multiple myeloma. They are β2-microglobulin, lactate dehydrogenase (LDH), cytogenetics, and plasma cell-specific FISH analysis (hyperdiploidy, t(4;14)(p16;q32), t(14;16)(q32;q23), 17p13, t (11;14)(q13;q32), 1q amplifications, 1p deletions, loss of 12p, gains of Cr5).

Table 2. Risk Classification Based on Baseline Testing

Of note that in the latest NCCN guideline about multiple myeloma several high-risk chromosomal aberrations in MM locates at 14q32, including three main ones that are t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Thus the risk incidence of t(11;14) is inconsistent with what was decribed in Table 2.

For this inconsistent two view I have sent an inquiry to NCCN and their answer was “We have reviewed your inquiry with the NCCN Guidelines Panel Chair, Dr. Kenneth Anderson. NCCN does not classify t(11;14) as high risk, it is only listed as a major group containing the 14q32 translocation. ”

And pay attention that patients with t(4;14), β2 microglobulin <4 mg/L and hemoglobin ≥10 g/dL may have intermediate risk disease.

Although the genetics can afford the prognosis of multiple myeloma, this approach still needs more evidence. At present the method is still the Durie-Salmon criteria or ISS criteria.

Table 3. Stage of Multiple Myeloma

As shown in the table 2 at left, the stage of multiple myeloma can be divided into three periods: stage I, stage II, and stage III.

The Management of Solitary Plasmacytoma

For those patients with osseous plasmacytoma, primary radiation therapy (45 Gy or more) to the involved field is the initial treatment and is potentially curative. Extraosseous plasmacytomas are treated initially with radiation therapy (45 Gy or more) to the involved field followed by surgery if necessary.

After radiation thearpy, patients with solitary plasmacytoma need follow-up. Blood and urine tests performed every 4 weeks initially to monitor response to the primary radiation therapy. If the patient achieves complete disappearance of the paraprotein then the frequency could be reduced to every 3-6 months or as indicated clinically. If the protein persists, then the monitoring should continue every 4 weeks. These tests include CBC, serum chemistry and those listed in the section of workup.

If progressive disease emerges, then the patient should be re-evaluated for recurrent plasmacytoma or myeloma, and systemic therapy administered as indicated.

The Management of Smoldering Myeloma

Although the activity of novel agents has advanced to the point that early interventions are now being explored in clinical trials for smoldering myeloma, there is still no evidence that early treatment will improve survival in asymptomatic and biochemically stable patients. A critical point is that up to 25% of smoldering myeloma patients will not require active treatment for 10 to 15 years. However, the majority will indeed progress during that time.

Once diagnosed, smoldering myeloma patients require frequent monitoring to allow treatment to begin before end-organ damage is evident. These tests are similar with solitary plasmacytoma, which are listed in the section of workup. If the disease progresses to symptomatic myeloma, these patients should be managed as active/symptomatic myeloma. We will discuss the management of active/symptomatic myeloma below.

The Management of Active/Symptomatic Myeloma

If the patients with MM progresse to active/symptomatic myeloma. Treatment should be initiated. Generally, we divide the treatment strategy into initial drug therapy, hematopoietic cell transplantation, and consolidation and maintenance thearpy after transplantation.

Therapeutic goal

There is a growing body of evidence showing an association between depth of response to therapy and improved long-term outcomes, including progressive-free survival (PFS) and overall survival (OS), in MM patients. Using conventional chemotherapy, it has been shown that there is a correlation between response before and after transplantation and that the quality of response after transplantation has a marked impact on outcome.

Importantly, studies suggest that if a patient achieves a complete response (CR), this must be durable and that the duration of CR is the best predictor of OS. However, some special cases makes the view that initially obtaining a CR in predicting long-term outcome questionable, for instance, group of rapidly responding but early relapsing patients, group of more indolent myelomas that revert to an “monoclonal gammopathy of uncertain significance like” profile after therapy, and group of myeloma patients with stable nonprogressive disease after induction therapy.

Initial drug therapy

Although success and long-term remission have been achieved in many transplantation-eligible patients using limited treatment regimens, such as thalidomide/dexamethasone, bortezomib/dexamethasone, and lenalidomide/dexamethasone, complete and very good partial response (VGPR) rates can be substantially increased by combining these various drugs in triplets or even using 4 drugs together.

On the right is the data of several clinical trials. I list all the detail of regimens below:

VAD: vincristine, adriamycin, and dexamethasone;

TD: thalidomide and dexamethasone;

RD: lenalidomide and dexamethasone;

PAD: bortezomib, doxorubicin, and dexamethasone;

VTD: bortezomib, thalidomide, and dexamethasone;

CVD: cyclophosphamide, bortezomib, and dexamethasone;

RVD: lenalidomide, bortezomib, and dexamethasone;

CVRD: cyclosphamide, bortezomib, lenalidomide, and dexamethasone.

A note of caution is that many of these studies are based on relatively small numbers of patients at single, or limited numbers, of centers, but cumulatively the message is consistent, with frequent, rapid, and deep responses seen.

Althought response rates are clearly improved with new drug cocktails, proving a consequent OS advantage is difficult and especially challenging given the large numbers of patients and the long duration of follow-up required. However, based upon response rates, depth of response achieved, and PFS as surrogates, 3-drug cocktails are currently the modality of choice in clinical practice, with use of RVD, CVD, or VTD as the most commonly chosen regimens outside of clinical trials.

Transplantation

Transplantation is a useful modality helping achieve or consolidating CR. But is it necessary to provide any consolidation chemotherapy before transplantation? If the patient is going to proceed to  transplantation, when do we implement the transplantation. However, because the goal of therapy is to maximize the depth and duration of remission, induction therapy can be continued in some patients for as long as the patient is responding and tolerating therapy, which might be instead of transplantation.

Generally ASCT is the primarily way of transplantation. Allo-SCT should infrequently be performed outside of clinical trials, as the risk of morbidity and early mortality of even nonmyeloablative transplantations is considerable.

Question one is whether to offer any consolidation chemotherapy before transplantation.

After initial induction thrapy, the subsequent approach is to provide further 4 to 6 cycles of induction threapy, then proceed eligible patients to ASCT. The reason to use stem cell transplantation is to provide a consolidation of remission after obtaining the best possible response to frontline treatment.

But a controversial area is what to do if the patient has already achieved a CR before transplantation. In this decision, the role of continued chemotherapy treatment versus proceeding to transplantation is less clear and an are of active research. Generally, in practice we prefer to proceed patients to transplantation without any further induction chemotherapy.

The reason to proceed to transplantation even achieving CR before transplantation is that current measures of CR are insufficiently sensitive and residual disease is in many, if not all, patients present but below the level of detection.

Question two is when do we offer stem cell transplantation to our patients who are eligible to this procedure. The timing of ASCT is also an area of active research. Patients are usually more fit for intensive therapy early in the course of the disease, but prior studies using conventional chemotherapy as induction demonstrated this a delayed ASCT had no adverse impact on OS and is feasible as part of salvage therapy in first relapse.

Maintenance therapy

Clinical studies found thalidomide maintenance to improve overall survival. Lenalidomide may offer the same advantages with less toxicity. Generally, it has become our practice to use maintenance routinely when patients have not achieved a CR after stem cell transplantation or when genetic risk markers suggest a very high risk of early relapse.

Figure 1. Respond Criteria for Multiple Myeloma

The Mangement of Relapsed AML

August 12, 2013 Chemotherapy, Hematology, Pharmacotherapy, Therapeutics, Transplantation No comments ,

The only cure of an adult with relapsed AML is a transplantation. However, three important questions shoul be solved when managing relapsed AML.

  1. Whether the patients with relapsed AML should receive a transplantation in untreated relapse rather than undergo reinduction therapy.
  2. Which regimen should be offered to patients with relapsed AML for the purpose of reinduction.
  3. Once the patient with relapsed AML achieve CR2, should conslidation be administered before transplantation.

Question One

In early relapse a transplantation can be performed safely with an outcome that is probably not significantly inferior to performing this in CR2. However, for relapsed AML patients who have a long duration of CR1, there is a greater than 50% chance of achieving CR2 and since it is always preferable to undergo a transplantation while in CR2. If, on the other hand, the duration of CR1 whould be less than 6 months, where the likelihood of achieving CR2 is no greater than 20%, patients with relapsed AML should be proceeded to an allogeneic 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.

Question Two

There is no evidence that any given regimen is superior and much of standard practice is guided by unsubstantiated opinion. Although in theory the use of a non-cross-resistant agent has intuitive appeal, there is no evidence that the efficacy of high-dose cytarabine as a salvage regimen is lessened by the prior use of this agent in consolidation, particularly after a long CR1. Furthermore, although commonly used with or without anthracyclines, etoposide, mitoxantrone, fludarabine, amsacrine, or asparaginase, there is no information collected prospectively to indicate that this is more efficacious than high-dose cytarabine alone. But of note that regimens that do not include cytarabine are equally effective for relapsed patients.

Question Three

For a patient in CR2, some investigators would add consolidation before an allogeneic transplantation if the patient is medically fit, even if this is not the practice in CR1. But some experts would elect to proceed directly to transplantation, with the primary consideration being to reduce transplantation-related toxicity.

The Management of Acute Lymphoblastic Leukemia in Adults (Stratetgies)

July 22, 2013 Chemotherapy, Hematology, Pharmacotherapy, Therapeutics, Transplantation No comments ,

Acute lymphoblastic leukemia (ALL) is a malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. ALL is a heterogeneous disease, both in terms of its pathology and the populations that it affects.

Prognostic Factors and Risk Categories

Several factors determine the prognosis of ALL in adults. These most important variables include initial white blood cell count, age at diagnosis, immunophenotype, genetic subset, extramedullary disease, and early treatment response/minimal residual disease.

35 years appears to be a clear prognostic cut-off. Age older than 35 years decreases the chance of remission as well as increases the risk of relapse in patients given conventional chemotherapy. Presenting white cell count (>30 × 109/L for B-cell disease and >100 × 109/L for T-cell disease) is a poor prognostic factor. Immunophenotype: T-cell disease has a better outcome than B-cell disease in adults.

Ph chromosome, t(4;11), t(8:14), complex karyotype (defined as 5 or more chromosomal abnormalities), or low hypodiploidy/near triploidy are also poor prognostic factors too. The presence of the Ph chromosome affects the chance of remission after induction, as well as the risk of relapse, when using conventional chemotherapy.

Minimal residual disease (MRD) in adult ALL could be detected by both molecular and immunophenotypic methods, which can reliably detect the presence of residual ALL at levels of less than 0.01%. The presence of detectable MRD by molecular methods after completion of both phases of induction predicts for a poor prognosis even in patients with standard-risk group. One study reported that patients with standard-risk ALL who had a rapid decline in MRD within the first month of therapy had a 0% 3-year relapse rate while those with molecular persistence of ALL by week 16 of therapy had a 94% 3-year relapse rate. Another study showed that > 8 weeks to CR1 was associated with a poor survival. In the MRC-ECOG UKALLXII/EC2993 trial time to attain CR > 4 weeks is defined as a high risk criteria.

However, the significance of many prognostic factors changes with improvements in treatment. For example, the outcome for both children and adults with Ph+ ALL has improved substantially with the addition of tyrosine kinase inhibitors to the treatment. Recently, children with Ph+ genotyp treated with chemotherapy and imatinib (without allo-SCT) had a 3-year event-free survival (EFS) of over 80%. If the favorable outcome is confirmed with longer follow-up, the Ph chromosome may join a long list of other factors such as male sex and African-American ethnicity that have lost adverse prognostic impact with improved treatment in childhood ALL.

More recently, the application of microarray-based, genome-wide analysis of gene expression and DNA copy number, complemented by transcriptional profiling, re-sequencing and epigenetic approaches, has identified specific genetic alterations with biologic and therapeutic implication.

Table 1 Prognostic Factors Used in Pediatric and Adult Clinical Trials

Of note that there are no “low risk” group in ALL. Instead, there are standard risk group and adverse risk group.

Molecular Monitoring For MRD

Several investigators have introduced more sensitive molecular techniques such as clonal immunoglobulin or T-cell receptor gene rearrangements to detect MRD that can accurately predict relapse in patients with ALL. Pediatricians have recognized that molecular persistence of residual ALL at the end of induction chemotherapy or afterward effectively predicted relapse independent of other risk factors.

Molecular marker monitoring has been used less extensively in adult ALL but appears to be an extremely powerful tool that has yet to be exploited.

Update from Medscape on Sep 19th 2013

Multiparameter flow cytometry and real-time quantitative polymerase chain reaction (qPCR) are two coming techniques that might make routinely monitoring for MRD possible. (Original from http://www.medscape.com/viewarticle/808782?nlid=32288_330&src=wnl_edit_medn_honc&uac=180112PN&spon=7)

Treatment Strategies for ALL

Contrary to the excellent results achieved in pediatric patients, the outcomes for ALL in adult patients are disappointing. While in recent multicenter trials more than 90% of adult patients with ALL younger than 60 years attain CR, conventional chemotherapy is a long arduous process and will result in long-term survival in only one-third of patients.

Treatment of ALL involves some of the most complex chemotherapy combinations and treatment schedules used in oncology. Induction chemotherapy is used first to reduce the burden of lymphoblasts in the bone marrow and to restore normal hematopoietic funtion. Consolidation therapy (also termed intensification) is used with the intention of clearing any drug-resistant leukemia cells that have survived induction therapy and to eliminate minimal residual disease (MRD). Maintenance chemotherapy consists of 2 to 3 years of low-dose antineoplastic drugs designed to prevent leukemia relapse during the crucial few years after remission induction and consolidation. Finally, central nervous system (CNS) prophylaxis is necessary to treat sanctuary sites that are shielded from systemic thearpy by the blood-brain barrier.

Induction Therapy

The induction chemotherapy is determined according to Ph status. For Ph-negative ALL patients, regimens comprise steroid, vincristine, and L-asparaginase, usually with anthracycline (up to 2 to 3 times the dose given in pediatric protocols) and often with the addition of cyclophosphamide and cyarabine. Comparable rates of complete remission (CR) of approximately 85% to 95% and treatment-related mortality (TRM) are seen in all published regimens, which is between 5% and 10% —— much higher than the <1% in children.

25% of all adults are Ph+ chromosome ALL. For Ph-positive patients with ALL, the induction therapy dose not differ from that for Ph-negative patients, except the addition of tyrosine kinase inhibitor (TKIs) imatinib. Studies show imatinib has improved the CR rate to >90% and makes more patients eligible for transplant. One studieMust to mention that in the latest NCCN guideline for ALL, the addition of one of TKIs to induction therapy, consolidation therapy, and maintenance therapy, respectively, has been the standard of care.

An alternative induction therapy is the hyper-CVAD regimen comprising hyper-fractionated cyclophosphamide, vincristine, doxorubicin (that is adriamycin), and dexamethasone, which reported a CR rate in excess of 90%.

Table 3 Common Chemotherapy Regimen for ALL

Regimen
BFM/COGvincristine, anthracycline, corticosteroid, L-asparaginase
CALGBvincristine, anthracycline, corticosteroid, L-asparaginase+cyclophosphamide
hyper-CVAD Ahyper-fractionated cyclophosphamide, vincristine, dexorubicin, dexamethasone
hyper-CVAD Bhigh-dose methotrexate, cytarabine

For adolescents young adults (AYA) with ALL, there are increasing data that suggests that this group of patients treated with adult ALL protocols have a worse outcome than similar patients treated on pediatric protocols (two studies, the age of enrolled patients are 15-21, 16-20, respectively). A “pediatric” approach to therapy gives superior survival than an adult approach in adolescents with ALL. According to a study published in the May issue of the American Journal of Hematology, Ron Ram et al. found that adolescent and young adult patients with acute lymphoblastic leukemia (ALL) who were treated with pediatric-inspired regimens exhibit lower all-cause mortality, higher complete remission and event-free survival rates, and lower relapse rates compared with those treated with conventional adult-chemotherapy regimens. Some results of certain trials are listed in Table 2.

However, definition of the age range that encompasses the AYA patient is itself controversial, because the age range described in the literature for this population varies depending on the study. In recent studies, the age range was set up to 30 yrs or even up to 40 yrs. Of note, the latest NCCN guideline for ALL suggests that the age of 40 is the cut-off between AYA and “older” adults.

Postremission Therapy

Consolidation/maintenance therapy for adults is based on that used in pediatric regimens. No randomized studies usefully address the benefits of the number or composition of consolidation cycles in adult ALL. Consolidation/intensification with high-dose methotrexate 1.5 to 3 g/m2, somethimes in conjunction with L-asp (L-asparaginase), is commonly used and is an important component of central nervous system (CNS)-directed therapy.

Maintenance therapy remains obligatory in those not undergoing allo-SCT. Daily mercaptopurine, weekly methotrexate and pluses of monthly vincristine and steroids for 18 to 24 months after consolidation is standard.

CNS-Directed Therapy

CNS involvement occurs in 5% of adults at diagnosis and although it impacts on survival (29% vs 38%; P = .03), it is unclear how much prophylactic CNS-directed therapy is required. Most protocols do not now give CNS irradiation, and 4 to 6 intrathecal doses of chemotherapy and high-dose methotrexate seem to be adequate to prevent CNS relapse. However, there are no data on the most efficacious drug or drug combination in adults to CNS-directed therapy. For patients proceeding to TBI-containing allograft regimens, intrathecal chemotherapy alone is sufficient. More prophylaxis may be required with RIC regimens, but this remains untested. CNS involvement is more common with high WBCs, T-cell disease, and a mediastinal mass.

The role of cranial irradiation in providing CNS-directed prophylaxis in adults is difficult to gauge. In the pediatric group, cranial irradiation is now used very infrequently. CNS relapse is now sufficiently infrequent as to render the numbers of patients required to evaluate this in a randomized manner pragmatically impossible.

Hematopoietic Stem Cell Transplantation

The decision to proceed to transplant for adult patients with acute lymphoblastic leukemia is not clear-cut. Relapse and nonrelapse mortality continue to plague the outcome of hematopoietic stem cell transplantation (HSCT) even when undertaken in CR. Those considered to be at high risk for relapse often are considered for HSCT in CR1 while those at lower risk may not be referred until they have relapsed, when their chances for cure are very poor.

During the past 14 years the MRC/ECOG study has assigned allo-SCT to all adult patients, including those with standard-risk ALL, who had an HLA-compatible sibling. The final data were recently reported and showed an unequivocal benefit for HLA-compatible sibling transplantation for patients with standard-risk ALL over other forms of conventional therapy, whether this is consolidation or maintenance therapy or an auto-SCT. The transplantation was performed as soon as possible after successful induction.

Table 4 Recommedations for HSCT of ALL Patients

However, there is a consideration that all standard-risk patients in MRC/ECOG trial were treated with a typical adult regimen rather than a pediatric-like regimen, so the benefit of allo-SCT for AYA group after indcution therapy of a pediatric-like regimen remains open. However, the data recently reported by Dana-Farber Cancer Institute in Boston, Massachusetts, for 51 adolescent patients aged 15 to 18 years showed a remarkable event-free survival of 78% in this population. This is clearly better than anything else that has been reported to date, and, if such data are confirmed in an unselected population, there clearly will be no role for an allogeneic transplantation in this age group.

Impact of Age to allo-HSCT

Although the risk of relapse decreases with allo-SCT, the concomitant treatment-related mortality (TRM) might eliminate the potential survival benefit under some conditions. TRM among “high-risk” patients was sufficient in magnitude to abrogate a survival advantage in this group despite the evident anti-leukemia activity of the procedure indicated by the reduction in relapse risk.

The UKALLXII/ECOG2993 study found that patients with sibling donors who were Ph-negative had an 8% higher chance of survival at 5 years, irrespective of risk status, but the benefit of allo-HSCT was apparently confined to those with “standard risk” disease. The reason for this might be that since one of the criteria for “high-risk” is age greater than 35 years and given that advancing age also confers the highest risk of TRM, this is probably the main reason for lack of survival advantage in the “high-risk” group. To date, the threshold at which TRM exceeds reduction in relapse risk may be as low as 35 to 40 years of age.

For high-risk Ph patients (age < 35 to 40) without sibling donor, whether the benefits of using a sibling-matched allogeneic HSCT can be extended to un-related donor allogeneic HSCT is still open and need more investigation.

Table 5 MRC-ECOG Trial: Outcome after allo-HSCT in Ph Patients

Allo-HSCT: Matched Unrelated Donor

Allo-HSCT is particularly effective in Ph+ patients.

Accumulated evidence of the very poor results of treating this disease with chemotherapy alone, accompanied by reports from retrospective series of allo-HSCT suggest that myeloablative therapy, with a TBI-based conditioning regimen followed by sibling allo-HSCT, represents the current best available treatment option for appropriately aged patients with Ph+ ALL in CR1. The MRC-ECOG UKALLXII/EC2993 trial for Ph-positive ALL patients undergoing URD allo-HSCT showed that  at 5 years there was no statistically significant difference in OS or in cause of death between those receiving sibling allo-HSCT and those receiving matched unrelated donor allo-HSCT.

Reduced-intensity Conditioned allo-HSCT

There are few publish large-scale data about the efficacy of reduced-intensity allografting for older patients with ALL. The success of RIC allo-HSCT is likely to be disease burden dependent; absence of MRD at the time of transplant may be of crucial importance although this has not been formally studied. Preliminary, retrospective data do not provide sufficient basis for recommending RIC allografts in older or more infirm patients with ALL in CR1. This approach merits consideration, but careful prospective study is still requried to define its role.

Autologous HSCT

The MRC-ECOG UKALLXII/E2993 trial compared 446 CR1 patients randomized to undergo either an autologous HSCT (N = 233) or 2.5 years of maintenance therapy (N = 223). EFS was statistically superior for the chemotherapy-treated patients, 42% versus 33% (P = .02). While OS also was improved in the chemotherapy group (47% versus 37%), in which the evidence showed that autografting in CR1 is inferior to continuous maintenance chemotherapy. An analysis of > 300 patients in three French trials also found no advantage for autografting. Therefore, routine use of autologous HSCT in adult patients with ALL is not recommended.

Table 5 Response Criteria for Acute Lymphoblastic Leukemia

Anti-infection Prophylaxis in Cancer Patients With Neutropenia (Drug Selection)

July 12, 2013 Chemotherapy, Hematology, Infectious Diseases, Pharmacotherapy, Therapeutics, Transplantation 19 comments , , ,

Because evidence was unavailable from trials limited to outpatients, the ASCO Panel considered evidence from studies on inpatients or mixed populations, and the recommendatons are based on the summarized evidence and Panel members’ expert opinion.

Antibacterial Prophylaxis

Majority of randomly assigned patients in studies were hospitalized and treated for hematolgic malignancies. Taken together, evidence shows that systemically absorbed fluoroquinolones are more tolerable than other antibacterials investigated for prophylaxis in neutropenic oncology patients and are as efficisous yet more tolerable when used alone as when combined with other antibacterials active against Gram-positive organisms. Of note, use of a nonabsorbable antibacterial also significantly increased the number of microbiologically documented infections, Gram-negative infections, Gram-positive infections, bactermia, and overall adverse effects.

The Panel recommends use of an orally administered, systemically absorbed fluoroquinolone for antibacterial prophylaxis. Prophylaxis should be administered from the first day of the cytotoxic antineoplastic regimen unitl myeloid reconstitution. However, routine antibacterial prophylaxis should be avoided when expected duration of neutropenia is < 7 days, the severity is less than profound, and none of the risk factors list in table 1 in the post of risk evaluation and patient selection are present.

Also if antibacterial prophylaxis is given, a strategy to systematically monitor for fluoroquinolone resistance among Gram-negative bacilli in environments where fluoroquinolones are being deployed.

Antifungal Prophylaxis

Results from clinical trial show that a majority of patients benefit from antifungal prophylaxis with orally absorbable or parenteral drugs versus controls receiving placebo, no treatment, or nonabsorbable oral drugs. These patients were at high risk for invasive Candida infection or aspergillosis resulting from long periods (≥ 7 days) of severe to profound neutropenia as a consequence of induction therapy for acute leukemia or HSCT.

The Panel recommends an orally administered triazole (fluconazole, itraconazole, posaconazole, or voriconazole) or an echinocandin administered parenterally (micafungin or caspofungin) for antifungal prophylaxis. Note that more trials of antifungal prophylaxis with more randomly assigned oncology patients at risk for IFIs have investigated fluconazole than any other orally absorbed or parenterally administered antifungal drug.

PCP Prophylaxis

Meta-analysis found that TMP-SMX decreased the incidence of documented PCP, and PCP-related mortality versus controls receiving placebo, no treatment, or an antibacterial drug inactive against Pneumocystis. Also, additional meta-analyses showed no statistically significant differences between those randomly assigned to TMP-SMX and those randomly assigned to placebo or no treatment with respect to any adverse events or adverse event causing patients to discontinue treatment.

The Panel recommends using any of the published daily, twice per week, or three times per week schedules of TMP-SMX during the period of immunodeficiency: from engraftment until day 180 for those undergoing allogeneic HSCT, from initiation of induction therapy in acute lymphoblastic leukemia until completion of all antileukemic therapy. For patients who may be hypersensitive or unable to tolerate TMP-SMX for any reasons, alternatives may include dapsone, aerosolized pentamidine, or atovaquone.

Virus Reactivation Prophylaxis

HBV

It is recommended that an antiviral nucleoside analog with demonstrated activity against HBV as prophylaxis for those at substantial risk for reactivation of HBV infection. Studies reported statistically significant decreases in HBV reactivation and HBV-related hepatitis with lamivudine prophylaxis in patients at risk. The approach is to start therapy 1 week before chemotherapy begins and continuing for at least 6 months after chemotherapy ends.

HSV and VZV

It is recommend to use a nucleoside analog to prevent herpesvirus infection in those at risk from the initiation of cytotoxic therapy until myeloid reconstitution.

Finally, influenza immunization is recommended for all patients undergoing treatment for malignancy and for all family and household contacts. Trivalent inactivated vaccine should be used. In select circumstances after proven exposure of a susceptible patient with cancer, a neuraminidase inhibitor may be offered.

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.