AGE NOT A BARRIER TO HSCT

Age is no longer a barrier to hemopoietic stem cell transplantation (HSCT), but ageism still exists, and many older patients are not being referred for a transplant, even though transplantation offers the only chance of a cure for hematologic malignancies.

Advances in transplant technology have greatly improved success rates, so that the outcomes in older patients are now similar to those seen in younger patients, as shown here in several presentations at the American Society of Hematology (ASH) 55th Annual Meeting.

"However, these advances have not penetrated through to the general oncology community and are not widely appreciated, so the idea persists that transplants are only feasible for younger patients (under 55 years of age)," commented Mary Horowitz, MD, scientific director of the Center for International Blood and Marrow Transplant Resercah (CIBMTR) and chief of the Division of Hematology and Oncology at the Medical College of Wisconsin, in Milwaukee.

"There are many 55- to 65-year-olds who could benefit from a transplant, but these patients are not being referred by their primary oncologist," she commented in an interview with Medscape Medical News. "A 60-year-old now would be expected to live to 85 or so, and if they suddenly develop a life-threatening disease that is curable, well it is worth trying to cure it," she said.

Age Not a Barrier

That chronologic age need no longer be a barrier was illustrated in a study reported at the meeting by Yvette Kasamon, MD, of the Johns Hopkins Kimmel Center in Baltimore, Maryland, and highlighted today in a conference press briefing.

Dr. Kasamon discussed data on 273 patients who underwent a haploidentical, or "half-matched," bone marrow transplant (BMT) without prior myeloablative therapy but with high-dose post- trasplantation cyclophosphamide. These patients had poor-risk hematologic malignancies (56% lymphoma, 35% acute leukemia or myelodysplastic syndrome, 9% other disorders), and 15% of patients had undergone autologous bone marrow transplantation.

"The similarly positive outcomes we observed among patients in their 50s, 60s, and 70s clearly illustrate that advanced age need no longer be a significant barrier to successful outcomes after half-matched BMT," Dr. Kasamon said.

All 3 age groups showed similar 2-year probability of progression-free survival (PFS) and overall survival (OS), and there was also no statistically significant difference in the risk for nonrelapse death or severe graft-vs-host disease.

Patients' Age (years)	Est 2-Year PFS	Est 2-Year OS
50 - 59	39%	51%
60 - 69	36%	56%
70 - 75	39%	44%

"These results underscore that a reduced-intensity, related haploidentical transplant should be considered a very reasonable treatment option for suitable patients up to at least age 75 who require a transplant," Dr. Kasamon said. In fact, she added, her clinic has recently raised the age limit to 75 years for a transplant.

However, she also noted that there are not many treatment centers that carry out haploidentical transplantations on a regular basis, and that, age aside, the successful outcomes in this study using this approach represent an advance in their own right.

Until recently, haploidentical transplants carried excessive risk, she pointed out. The use of post-transplant cyclophosphamide for prophylaxis of graft-vs-host disease has been a major advance, she said, and with the use of this treatment, haploidentical transplantation has become a safe and effective treatment in the outpatient setting.

The outcomes with haploidentical transplants with post-transplant cyclophosphamide are now similar to those seen with matched BMT, Dr. Kasamon added.

Chimeric Antigen Receptor-CAR LYMPHOCYTES A NEW PROMISING TREATMENT

There is palpable excitement here at American Society of Hematology (ASH) 55th Annual Meeting over results that are being reported with a new approach to treatment, engineered T cells. Although the results come from pilot clinical trials conducted in a small number of patients with leukemia and lymphoma, these are patients with very aggressive and refractory disease, and yet some of them have shown dramatic responses to the therapy, going into complete remission and no longer showing visible signs of tumor on computed tomography (CT) scans.

"It looks like the disease has disappeared after a single infusion of these engineered T cells," commented James Kochenderfer, MD, from the Experimental Transplantation and Immunology Branch of the National Cancer Institute (NCI) in Bethesda, Maryland.

However, he cautioned that there is a significant patient variation in both efficacy and toxicity with this approach.

Several groups in the United States are working on this approach to treatment, and some have teamed up with pharmaceutical companies. The T cells developed at NCI have been licensed to Kite Pharmaceuticals, and a similar approach developed at the University of Pennsylvania, which has the most clinical data so far, has been licensed to Novartis.

Some observers say that this pharmaceutical company involvement, as well as accelerated approval for an urgent medical need, could result in these therapies becoming available as early as 2016, but others forecast a longer development time and suggest the therapies will not be available for clinical use until 2020.

Like a Smart Bomb

The novel approach to therapy involves extracting T cells from the patient, subjecting the cells to chimeric antigen receptor (CAR) cell engineering, and then infusing the engineered T cells back into the patient.

The engineering, which takes about 10 days, changes the T cell in 2 ways. First, it adds a receptor that targets the CD19 antigen that is found on most leukemic cells; when the cells are inserted back into the patient’s body, they home in on this antigen, latch on and destroy the leukemic cell. Second, the process inserts a viral vector mechanism into the cells which – once the cells have latched on to the leukemia – triggers these T cells to expand and proliferate, so that they seek out and destroy all the remaining leukemic cells.

There is tremendous excitement over this approach, because it acts like a smart bomb, said Mary Horowitz, MD, scientific director at the Center for International Blood and Marrow Transplant Research and chief of the Division of Hematology and Oncology at the Medical College of Wisconsin, in Milwaukee. Whereas bone marrow transplantation is like carpet bombing of a city in order to destroy a specific building, these CAR cells are like smart bombs that seek out and destroy just the building, she commented to Medscape Medical News.

The clinical results have been dramatic and unprecedented in such advanced disease.

Results in Lymphoma

Dr. Kochenderfer presented results from 15 adult patients with advanced B cell lymphomas (abstract 168), including 9 patients with chemotherapy-refractory large cell lymphoma such as primary mediastinal B cell lymphoma and diffuse B cell lymphoma. They received reduced-intensity conditioning with cyclophosphamide and fludarabine and then an infusion of their own T cells that had been CAR engineered.

Thirteen of the 15 patients treated were evaluable for response, and 12 of those 13 responded: 7 patients had complete remissions, and 5 had partial remissions, Dr. Kochenderfer said. The remaining patients had stable disease.

Dr. Kochenderfer gave details of one of the patients who had a complete remission, showing CT scans with visible tumor in the liver and abdomen prior to the treatment, and none visible after treatment. This was a patient who had undergone 10 prior therapies, including many different combinations of rituximab plus chemotherapy regimens, and the disease progressed a month after chemotherapy finished, so she was "clearly refractory," he said.

"Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable," Dr. Kochenderfer told journalists at an ASH press briefing at which these novel therapies were highlighted.

"We are particularly encouraged by the partial and complete responses that we observed in a number of patients with diffuse large B cell lymphomas who had exhausted all other treatment options…and who are not generally thought to be good candidates for hematopoietic stem cell transplantation," he added.

However, he tempered his enthusiasm by adding that "this approach is still an early-stage experimental therapy."

ORAL ARSENIC AS GOOD AS IV FOR APL

An oral arsenic-based formula treats acute promyelocytic leukemia (APL) as effectively as an IV formulation, auguring the promise of out-patient treatment for this condition, Chinese researchers say.

In a multicenter phase III trial reported online October 14 in the Journal of Clinical Oncology, they compared the oral formula, Realgar-Indigo naturalis (RIF) containing tetra-arsenic tetra-sulfide (As4 S4), to intravenous arsenic trioxide (ATO), for induction and maintenance.

The components of RIF include Indigo naturalis and Radix salviae miltiorrhizae, which promote transport of arsenics intracellularly. Triggered by higher aquaglyceroporin 9 (AQP9) expression, they have clear synergistic effects with As4S4 on the differentiation and apoptosis of APL cells, according to senior author Dr. Xiao-Jun Huang of the Peking University People's Hospital in Beijing and colleagues.

In all, 242 patients with newly-diagnosed APL were randomly assigned to oral RIF (60 mg/kg) or ATO (0.16 mg/kg). All patients also received all-trans retinoic acid (ATRA; 25 mg/m2) during induction therapy.

Patients who achieved complete remission (CR) then received consolidation chemotherapy with homoharringtonine, cytarabine, daunorubicin, and mitoxantrone.

Maintenance treatment consisted of sequential ATRA plus either RIF or ATO for two years.

The primary end point was the rate of disease-free survival (DFS) at two years, which was assessed for noninferiority with a 10% noninferiority margin.

After a median follow-up time of 39 months the results show DFS at two years was 98.1% (106 of 108) in the RIF group and 95.5% (107 of 112) in the ATO group. The DFS difference was 2.6%, and the lower limit of the 95% CI of DFS difference was greater than the 10% noninferiority margin, confirming noninferiority (p<0 .001="" p="">

No significant differences were noted between the RIF and ATO groups in complete remission rate (99.1% vs 97.2%; p=0.62) or in overall survival at 3 years (99.1% vs 96.6%; p<0 .18="" p="">

Rates of adverse events were similar in the two groups.

The authors also note that the toxicity of arsenic-containing agents is a major concern. However, this study showed no severe adverse effects despite the two-year continuation period, with a cumulative dose of approximately 2,500 mg.

Analysis of arsenic levels in the plasma, urine, nails, and hair of patients indicated that there was no significant accumulation.

The authors note that previous studies have shown, as did theirs, that the frequency and extent of arsenic toxicity are much milder during maintenance therapy than during induction therapy.

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"Other contributing factors were sufficient support therapy, enrolling only patients with a white blood cell count less than 50x10 to the 9th per liter, favorable characteristics of the enrolled patients (good performance status and exclusion of patients older than age 60 years), and experience in treating APL22; the latter is recognized as a potentially important factor in the outcome," the authors write.

Acute promyelocytic leukemia (APL) is characterized by the translocation t(15;17) and the expression of a PML/RAR alpha fusion protein that is diagnostic of the disease. To closely observe the molecular kinetics, the study authors also analyzed serial bone marrow samples from 93 patients. Expression of PML-RAR alpha in the RIF and ATO groups was similar at diagnosis.

They found, at the end of consolidation therapy, that the PML-RAR transcript was undetectable in any patient in either group. The two relapsed patients had detectable PML-RAR transcript levels before hematologic relapse.

The authors conclude "oral RIF plus ATRA is not inferior to intravenous ATO plus ATRA as first-line treatment of APL and may be considered as a routine treatment option for appropriate patients."

Dr. Francesco Lo-Coco, a hematologist at the University of Tor Vergata in Rome and an expert on the use of arsenic trioxide in PML, told Reuters Health by email that the study was well-conducted and represented "remarkable progress."

"This study hold promise that in the near future we will be able to cure APL not only sparing chemo but also on an outpatient basis (after the initial two to three weeks, when patients have to stay in hospital given the hemorrhagic risk)," Dr. Lo-Coco said.

He says toxicity profiles are similar and patients receiving the oral treatment will clearly have better quality of life.

"In fact, the IV infusion patients have to spend almost half a day in hospital each day. This affects negatively their normal life, work and other activities," he writes.

He says that just because the authors of the present study did not include patients older than 60 years, does not mean it doesn't work in the elderly.

"We know from other studies it works equally well," he said.

NO EVIDENCE FOR ORAL CANCER SCREENING

The evidence is insufficient to assess the balance of benefits and harms of screening by primary care providers for oral cancer in asymptomatic adults, according to updated guidelines from Virginia A. Moyer, MD, MPH, on behalf of the US Preventive Services Task Force (USPSTF). The guidelines will be published online November 26 in the Annals of Internal Medicine.

"According to National Cancer Institute data, the estimated new cases and deaths from oral cancer (oral cavity and pharynx) in the United States in 2013 is 41,380 new cases and 7890 related deaths," Dipika Bumb, BDS, MDS, an oral oncologist and tobacco control officer at the Indian Cancer Society in New Delhi, India, told Medscape Medical News when asked for independent comment. "The burden of disease is not less."

Squamous cell carcinoma accounts for 90% of all cases of oral cavity and pharyngeal cancer. More than half of persons with oral and pharyngeal cancer have regional or distant metastases when they are first diagnosed. The USPSTF therefore stated that screening for oral cancer may be helpful if potentially malignant disorders can be identified earlier and treated successfully.

"In clinical practice, screening can help in detection of oral cancer at a very early stage, where the lesions are either reversible or can be treated efficiently," Dr. Bumb said. "The changes occur at a slower pace in oral mucosa, [but the need for] oral cancer screening lacks recognition all over the world. Awareness among the medical community and government is the need of the hour."

USPSTF Deems Evidence to Be Insufficient

The revised guidelines, which update the 2004 USPSTF recommendation on screening for oral cancer, apply to screening of the oral cavity performed by primary care providers, and not by dental providers or otolaryngologists. The USPSTF reviewed the evidence both on whether screening for oral cancer was associated with lower morbidity or mortality and on the accuracy of the oral screening examination to detect oral cancer or potentially malignant disorders that are highly likely to progress to oral cancer.

On the basis of this evidence review, the USPSTF concluded that the current evidence was insufficient to evaluate the balance of benefits and harms of screening for oral cancer in asymptomatic adults aged 18 years or older who are seen by primary care providers. This is an I-level statement.

However, the USPSTF recognizes that clinical decisions, as well as policy and coverage decisions, involve more considerations than evidence of clinical benefits and harms alone. Therefore, clinicians should individualize decision making to the specific patient or situation.

"Potentially malignant disorders can be detected by visual examination by trained clinicians," Dr. Bumb said."The agony of the situation is that clinicians don't realize this, leading to late diagnosis and referral. During screening, the habit of tobacco and alcohol use can be regulated by professional counseling, leading to reduction in risk for other noncommunicable diseases."

The USPSTF found inadequate evidence that the oral screening examination accurately detects oral cancer or that screening for oral cancer and treatment of screen-detected oral cancer reduces morbidity or mortality. Furthermore, they found inadequate evidence on the harms of screening, as no study reported on harms from the screening test, from false-negative results, or from false-positive results leading to unnecessary surgery, radiation, and chemotherapy.

Because the natural history of screen-detected oral cancer or potentially malignant disorders is unclear, the degree of overdiagnosis resulting from screening is unknown.

Potential Harms of Not Screening

If practitioners stop screening for oral cancer, Dr. Bumb is concerned about the following potential consequences:

• Abandoning screening could substantially increase the incidence of oral cancer and other tobacco/alcohol/HPV-related disorders in the young population.
• Tobacco and alcohol cessation could become difficult, with interrelated addiction leading to further deterioration of health.
• Treatment of oral cancer not detected until late in the course results in disfigurement and disability of the face and neck.
• Treatment of oral cancer not detected until late in the course hinders delivery of palliative care and harms the individual's psychological integrity.

"In developing countries like India, oral cancer accounts for 95% of all cancers, and screening serves as the best tool in reduction of mortality and morbidity," Dr. Bumb said. "Like breast lumps are helpful in detection of breast cancer at an early stage, similarly, oral potentially malignant disorders (OPMD) are a stepping stone towards development of oral cancer."

Prostate terminology bewilders many inner-city men

Many inner-city men don't understand basic terms having to do with the prostate, according to a new survey, which could make it difficult for them to decide on treatment options for related cancers.

"The risk to benefit ratio of prostate cancer screening and treatment depend a lot on patient preferences, so it is critical that patients can understand the tradeoffs that are involved," said Dr. Stacey Loeb, a urologist at NYU Langone Medical Center in New York.

"This is particularly true for high-risk groups such as African Americans, who are known to be at greater risk for aggressive prostate cancer," Loeb, who was not involved in the study, told Reuters Health.

Another study this year indicated that the educational materials and websites doctors direct patients to are still too difficult for many patients to understand (see Reuters Health story of May 20, 2013 here: http://reut.rs/11cXHeQ).

Prostate cancer is the second leading cause of cancer death for men in the U.S., killing about 30,000 men each year according to the Centers for Disease Control. It's not always aggressive, however, meaning that men may be subjected to surgery or radiation, and side effects, without necessarily extending their lives.

Researchers distributed "pop quiz" surveys on common terms related to urinary, bowel and sexual functions at two clinics for low-income patients.

Of 109 men, 95 percent did not understand what the prostate does, according to results published in the journal Cancer. The numbers were better but still low for terms like "incontinence," "urinary function" and "bowel habits."

Many of the men read at a 9th-grade level.

"As our results indicate, most physicians likely overestimate patient understanding of these terms," coauthor Dr. Ashesh Jani told Reuters Health by email.

Prostate cancer can be confusing even for men with high literacy, said Jani, a radiation oncologist treating prostate cancers at Winship Cancer Institute of Emory University in Atlanta.

These results are "exactly what I would expect," according to Dr. Mack Roach, chair of radiation oncology at the University of California, San Francisco Medical Center.

But he's not necessarily worried about the patients as long as they're cared for by quality doctors, said Roach, who was not involved in the study.

"Allowing (patients) to feel comfortable about asking questions is most important, but this depends on the doctor," Roach said.

"For practicing clinicians, this is very important information," Dr. Durado Brooks of the American Cancer Society in Salt Lake City, Utah, told Reuters Health.

He found the numbers in this study "a little shocking," and stressed that doctors need to assess how much a patient understands, since some are embarrassed by their lack of knowledge.

Patients with low knowledge levels could jeopardize the patient half of "shared decision making," the collaborative process between patient and physician to come to a treatment decision, Loeb said.

"However, it is important to note that most of the men in this study did not have prostate cancer," she said. "Many people without any previous knowledge about a medical problem will read up on it if they are diagnosed."