Joseph Alvarnas, MD

Yes
You have come upon the fabled lands where myths
Go when they die.


— James Fenton
The Pitt-Rivers Museum (1983)

As a medical student, I was struck by the number of times our teachers regaled us with the “Gordian Knot” myth as a paradigm for how we should approach understanding complex patients and seemingly indecipherable clinical data sets. As legend has it, the Gordian Knot was so complex that it was impossible to perceive where one strand began and another ended; thus, it could never be unraveled. The task was considered so great that anyone who could untie the knot was prophesized to become the ruler of a vast portion of the world as it was then known. According to one version of the legend, Alexander the Great considered the knot, and in a stroke of genius pulled out his sword and sliced the knot in half. In doing so he fulfilled the oracle’s prophesy. The lesson of this story, as espoused by my teachers, was that a simple solution frequently existed for most complex healthcare conundrums.


We now find ourselves in the midst of a golden era of cancer care in which insights gleaned from genomic data and our ability to leverage a growing armamentarium of targeted anti-cancer treatments routinely produce superior survival outcomes with an improved quality of life for many patients. Yet, these advances have come with questions and challenges about how to pay for these treatments, how to deliver them equitably to patients in need, and how to ensure that our systems of care become more patient-centered. Clinical reimbursement systems now repeatedly lag advances in cancer diagnostic and treatment technologies. The cost of some treatments (such as CAR T-cell therapies) have challenged existing payment models from both public and private payers. At the same time, our care portfolio continues to outpace our systems for delivering this care in financially sustainable ways. Rather than empower a path toward sustainable solutions, the naïve believe that a simple approach is possible. This has paralyzed us from coming to terms with the necessary complexity of what it will take to deliver precision medicine solutions to cancer patients in the future. It is time for the mythic “Gordian Knot” approach to the development of more effective and efficient cancer care delivery systems to die.

™ we look at the emergence of additional innovative anti-cancer treatments, such as the second generation of the BTK inhibitors, DNA-based therapies for glioblastoma patients, and the clinical opportunities for the detection of NRG1 gene fusion in selected patients. Beyond exploring new diagnostic and therapeutic opportunities for cancer patients, we also review the exciting potential avenues for how healthcare payment and clinical reimbursement might evolve to support sustainable delivery of innovative treatments. Mark Trusheim, MSc, of MIT discusses a long-awaited plan to improve the ability of Medicaid programs to pay for gene-based therapeutics. Keely Macmillan, MSPH, from Archway Health discusses how downside risk related to precision oncology and high-cost therapeutics can be sustainably managed in the context of oncology advanced alternative payment models.


As the practice and systems-based delivery of cancer care evolves at a breakneck pace, simple solutions are more likely to harm, than help, essential stakeholders. Effective new delivery and payment systems can only emerge, however, if healthcare leaders fully embrace the inescapable necessary complexity of creating these systems. The writer HL Mencken cynically noted that, “For every complex problem there is an answer that is clear, simple and wrong.” There are many avenues in which the “Gordian Knot” approach leads to false choices and ill-conceived simple solutions. Pithy myths are a poor paradigm for navigating complex dilemmas. The path toward the broad realization of innovative, financially sustainable, equitably-delivered cancer care is likely to be an arduous, painful journey. It is time to embrace that complexity and let the comforting myths die.

Articles

From the Editor-in-Chief, Evidence-Based Oncology, August 2020.

Where Myths Go to Die

In the early days of AIDS, I trained as a medical student in a ward filled with patients struggling to survive complications of the illness. At that time, a large share of patients succumbed to their first episode of Pneumocystis pneumonia, and here were dozens of people struggling through this infection. So many frightened people, so many gaunt faces searching for hope.

In what could have been a center of despair, one patient, a professional singer, decided to fight back. Each morning, despite fatigue and shortness of breath, he stepped into the corridor and began to sing. At first the notes were tentative, interrupted by fits of coughing. As the days passed, however, his voice grew stronger, and the notes turned into increasingly beautiful arias. The beauty of the voice mesmerized and inspired us. This community, assembled through the cruel human toll of an invisible foe, was forged together through courage, gifted to us by one man’s willingness to fi ght back. Thirty-three years later, I can still hear his voice.

In both that pandemic and the one that we now face, our extraordinary systems of technology and knowledge have proven vulnerable to the smallest of things. Once again, we face an invisible, seemingly implacable foe that has upended our sense of normalcy. We should not resign ourselves to an inevitable fate, nor should we minimize the challenges of the road ahead.

As a hematologist, I have learned to appreciate that distinct moment in caring for patients and families, shortly after the word “cancer” is first spoken, that is both a time of extraordinary vulnerability and a turning point: It is the time when the will to transcend that word and its implications is mobilized in earnest.

We are at that moment in this pandemic. Clinicians, clinics, and hospitals have mobilized to ensure that patients receive the support and care that they require. In such a diffi cult time, it is extraordinary to see again and again how acts of compassion and courage can have such immense power. For those who are most vulnerable to the eff ects of the coronavirus 2019 (COVID-19), particularly those with cancer, hospitals and clinicians have worked to create safe havens where patients can continue to receive lifesaving care. As we learn more about this virus, with a flood of knowledge coming on a daily (sometimes hourly) basis, our ability to respond continues to evolve.

While this response is built upon a foundation of science and technology, the way forward ultimately requires that we navigate the human dimensions of this pandemic. Social distancing, masks, and a profound revisioning of our daily routines are as fundamental to transcending this virus as are much-needed advances in science and technology.

As I recall the early days of the HIV/AIDS pandemic, what stands out most is its profound human cost and the courage of those who helped our society transcend it. We are in the midst of a time in which the human toll of COVID-19 and the enormity of the path ahead are clear. As we develop the science and therapeutics necessary to combat this foe more eff ectively, we need to remember that success requires understanding and navigating the humanity at the heart of our systems of care. This battle is not going to be won fully in a laboratory—rather, it must be realized in the lives of real people.

As I recall the early days of the HIV/AIDS pandemic, what stands out most is its profound human cost and the courage of those who helped our society transcend it. We are in the midst of a time in which the human toll of COVID-19 and the enormity of the path ahead are clear.

From the Editor-in-Chief: Bigger Questions of Systems, Viruses, and the Lives of Real People

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References:  Humility and Hope: Evolution of the HIV Pandemic, From ART to Today’s Cancer Cures

References for Humility and Hope, Alvarnas

 described 5 previously healthy young men with 

(now P. jiroveci) pneumonia who, following case review by regional monitors from the CDC, seemed to have “cellular-immune dysfunction related to a common exposure.”

The Epidemiology Intelligence Service officer investigating these patients postulated that this represented “a ‘disease acquired through sexual contact.’”

 Over the next year and a half, similar reports would emerge from San Francisco, New York, London, and Paris.

 By late August 1981, the CDC had described 108 similar cases that now also included aggressive presentations of an uncommon cancer, Kaposi sarcoma.

 As more case reports accumulated worldwide, there was increasing evidence for a transmissible agent responsible for these growing clusters of severely immunocompromised patients. In September 1982 the CDC used the term acquired immunodeficiency syndrome (AIDS) for the first time to describe the condition.

This publication also included the first case definition for AIDS.

 By April 1984, the retrovirus responsible for AIDS was finally identified.

 By the end of the decade, 100,000 cases of patients with AIDS had been reported in the United States.

The origins of the human immunodeficiency virus (HIV)/AIDS pandemic, however, far precede the initial 1981 case reports. A phylogenetic analysis of HIV-1 points toward a species jump as the initiating event of the pandemic. A variant of the simian immunodeficiency virus found in a subspecies of chimpanzees (Pan troglodytes verus) displays striking similarity to HIV-1.

 This analysis proposes that multiple jumps from simian to human hosts occurred sometime in the late 19th to early 20th century, most likely in a remote region of southeastern Cameroon.

The first documented case of HIV dates to 1959 from plasma samples of a patient with sickle cell disease from Kinshasa in the Democratic Republic of Congo.

 The virus likely spread for more than 5 decades prior to its clinical recognition.

 The first retrospectively documented case of HIV/AIDS in the United States dates back to 1969.

Over the past 39 years, more than 75 million people worldwide have been infected with HIV; at least 32 million of them have died (data on numbers of people in the developing world with HIV are expressed as ranges).

 Prior to the availability of effective anti-HIV treatment, HIV/AIDS-related mortality grew annually. In 1995, 50,140 people died in the United States from complications related to HIV infection.

 By 1996, a dramatic advance in the care of HIV-infected patients changed the prognosis and, in time, what it meant to live with HIV infection. The development of highly active antiretroviral treatment (HAART) regimens produced a profound suppression in measurable levels of HIV in the bloodstream. For many individuals, this led to numerical restoration of CD4+ T cells and recovery of immunological competency.

HAART entailed a strategy to administer a combination of classes of antiretroviral agents that were targeted at different parts of the viral lifecycle. HAART regimens may include non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, and/or integrase inhibitors.

In a single year from 1995 to 1996, HIV/AIDS-related deaths decreased by 23%.

 Improvements in HIV/AIDS-related mortality continue through today: Between 1987 and 2015, age-adjusted death rates for patients living with AIDS have declined from approximately 375 per 1000 people living with AIDS to fewer than 25.21 The National Institutes of Health estimate that effective antiretroviral treatment (ART) treatment of HIV has, in the United States alone, saved more than 3 million years of life.

At present, nearly 38 million people worldwide live with HIV/AIDS.

 As effective anti-HIV treatments have evolved, they have been alternatively called HAART, combination ART, and more recently, simply ART, now the preferred term. Nearly 40 years into the HIV pandemic, despite the broad availability of effective ART, and outside of 2 known individuals who were successfully treated with allogeneic hematopoietic cell transplantation (allo-HCT) that cleared their respective HIV infections, there is still no evidence for a cure for HIV.

While effective ART has profoundly reduced the mortality rate and transmission of HIV, and antiretroviral preemptive treatments have provided at-risk individuals with an effective risk reduction tool, the virus continues to take an insidious, inexorable toll upon humanity.

 This includes, even in effectively treated individuals, an increased incidence of a number of different cancer types, end-organ injury, and an increased risk of premature death. In addition, lack of access to diagnostic testing and to effective treatment, as well as the impact of numerous social determinants of health, culminate in continued HIV-related mortality. In 2018, 770,000 people worldwide died from complications related to HIV/AIDS.

The connections between cancer and HIV/AIDS became clear relatively early in the HIV/AIDS pandemic. Not only were opportunistic infections present in a majority of HIV-infected patients who met the initial diagnostic criteria for AIDS, but several cancer types were far more prevalent as well. These included both cancers that occurred more commonly in severely immunocompromised patients and those that reflected a role for viral coinfection with oncogenic viruses (ie, human herpesvirus-8, human papillomavirus, Epstein-Barr virus, hepatitis B virus). The current diagnostic criteria for stage III HIV infection include invasive cervical cancer, Kaposi sarcoma, and lymphomas (Burkitt, immunoblastic, and primary central nervous system [CNS]) as stigmata of the disease that, in combination with confirmed HIV infection, establish the diagnosis of AIDS.

Early in the HIV pandemic, prior to the availability of effective anti-HIV treatment, infected patients sometimes presented with relatively unusual lymphoma subtypes, including those typically limited to individuals with severe immunocompromisation (primary CNS lymphoma, primary effusion lymphoma, plasmablastic lymphoma of the oral cavity, and polymorphic B-cell lymphoma).

 The spectrum of lymphoma types shifted and these relatively rare lymphomas are now less commonly seen. However, patients with effectively treated HIV still remain at an increased risk of non-Hodgkin lymphoma (NHL); the risk has dropped significantly in the post-ART era, but it remains more than 8 times higher than in the non—HIV-infected population.

Moreover, HIV-infected patients with lymphoma are still more likely to present with advanced-stage disease, to have involvement at extranodal sites (including a higher risk of central nervous system involvement), and to manifest systemic “B symptoms” at diagnosis.

Beyond those malignancies that represent AIDS-confirming diagnoses, population-based data for HIV-infected individuals show that there is a more broadly increased risk for a number of cancer types that are not included as part of the AIDS diagnostic criteria. The Swiss Cohort Study was based on a population-based registry, initiated in 1988, that includes 15,624 patients. The study evaluated not only cancer risk, but additionally provided insights into patterns of transmission, effectiveness of ART, pregnancy outcomes, and patient outcomes.

 A 2005 review of the registry data confirmed the increased risk of cancer among HIV-infected individuals. Beyond those increased risks for NHL, cervical cancer, and Kaposi sarcoma that were included in the AIDS diagnostic criteria, these population-based data confirmed an elevated risk for a broader set of cancer diagnoses, including Hodgkin lymphoma; cancers of the aerodigestive tract, anus, liver, and lung; and melanoma and nonmelanoma skin cancers.

 For cancers of the aerodigestive tract and lung, this increased risk was limited to smokers. The implications of these data are significant in the post-ART era. The authors of the study noted that “HAART treatment may prevent excess risk of [Kaposi sarcoma] and non-Hodgkin lymphoma, but not that of Hodgkin lymphoma or other non—AIDS-defining cancers.”

Effective cancer prevention for this population therefore includes a risk-adapted screening approach that integrates an awareness of the increased risk of cancer development related to HIV, and it also focuses upon modification of reducible risk factors, like smoking, that may be of enhanced importance for this population. 

Prior to the advent of effective anti-HIV treatments, the care of patients with HIV-related lymphomas frequently included dose-attenuated or deescalated regimens that produced poor survival outcomes.

Following the widespread availability of ART, numerous trials have validated the concept that effectively treated HIV-infected patients may be managed with standard cancer treatment regimens in a manner analogous to those patients without HIV.

This approach produces survival outcomes comparable with those of noninfected patients.

Some evidence indicates that concomitant treatment with effective ART produces better treatment outcomes.

 Moreover, ART-responsive HIV-infected patients with relapsed, refractory, or persistent blood cancers who otherwise meet transplant inclusion criteria appear to have survival outcomes with autologous HCT and allo-HCT equivalent to those without HIV infection.

 No evidence exists to indicate that therapy with standard treatment has a deleterious effect upon long-term HIV virologic control nor T-cell reconstitution. Patients may, however, develop short-term numerical drops in CD4+ T-cell counts such that they may require prophylaxis against opportunistic infections. When treating this population of patients with standard chemotherapeutic/immunotherapeutic regimens, it is also very important to review the ART regimen carefully, because there is potential for life-threatening drug—drug interactions between these respective regimens.

While enormous progress has been made to date against HIV, complete victory has been elusive. In 2018, 37,832 people were newly diagnosed with HIV infection in the United States. New infections are disproportionately occurring in the southern United States, and African Americans and Latinos now account for a majority of newly diagnosed patients.

The 2 individuals who have achieved documented cures of their HIV infection did so through a process that is likely not replicable on a scalable basis. To date, there are still no effective vaccines against HIV.

A key impediment to further progress lies within the unique biology of RNA lentiviruses. Sharp and Hahn note, “HIV-1 evolves around 1 million times faster than mammalian DNA… because the HIV-1 reverse transcriptase is error-prone and the viral generation time is short.”

 This may result in frequent changes to potential antigenic targets, thus limiting the potential effectiveness of candidate vaccines. Moreover, while vaccine-generated neutralizing antibodies may be effective for many viral infections, an antibody response alone may not be adequate to achieve full protection against HIV infection.

 An effective immune-prophylactic approach to HIV will likely require the generation of a cytotoxic T-lymphocyte response to the virus.

 In addition, the latent phase of the HIV viral lifecycle may render a significant part of the viral reservoir immunologically invisible, thus reducing the effectiveness of either humoral or cellular immunological responses to HIV. Finally, the complex logistics and economics of vaccine development further complicate the prospects for an effective anti-HIV vaccine.

While there is still much to understand before HIV is fully conquered, we have already learned a great deal about the pathobiology of this virus that has helped advanced immune-oncological technologies and led to the development of increasingly effective gene therapy delivery systems (

). HIV is a positive-sense RNA lentivirus that efficiently enters CD4+ T-cells; it undergoes reverse transcription to form DNA, which is integrated into host DNA prior to replication, assembly, and subsequent release into the bloodstream.

 Fortunately, this viral lifecycle can be co-opted for the vector-based gene modification of novel cellular therapeutics or used as a primary delivery system for in vitro or in vivo therapeutic gene modification.

 Removal of potential pathogenic genes from the lentivirus can allow for effective Good Manufacturing Practice production of the lentiviral vector, as well as for efficient target cell transfection with neogenes and reproducible clinical activity for the vector.

 This set of technologies is currently used to produce anticancer chimeric antigen receptor T-cell therapeutics for both commercial and investigational purposes.

Lentiviral vectors may also be used as the basis for investigational gene therapy—based treatment for patients with hemoglobinopathies and hemophilia.

 The AIDS Quilt was conceived in 1985 as a memorial, with each panel representing and documenting a person who lost their life to the HIV/AIDS pandemic. The AIDS Quilt became so large in 2012 that it was moved into a virtual form. At that time, the quilt spanned more than 1.3 million square feet and captured more than 94,000 lives lost to HIV. It is a graphic representation of the scale of devastation and suffering left in the wake of the HIV virus.

With the breadth of resources now available, the prospects for an eventual eradication of human HIV infection seem real—yet still painfully distant. Effective antiviral treatment, earlier diagnosis, behavioral modification, preexposure prophylaxis, and continued advances in vaccine development are the keys to a future without HIV. Advances in HIV treatment, more effective treatments for HIV-infected patients with cancer, and the continued pursuit of further therapeutic innovations for this population of patients portend a future of better cancer care outcomes and more effective cancer prevention. The pain and progress of the past 39 years have led to scientific advances that have implications far beyond the control of HIV infection. As we pause to remember the humanity at the center of all this progress, it is best to look forward with both humility and hope.

Joseph Alvarnas, MD, is vice president of government affairs, senior medical director, employer strategy, and associate clinical professor, Hematology & Hematologic Cell Transplantation, City of Hope.

See full reference list online at AJMC.COM/LINK/4669.

The connections between cancer and HIV/AIDS became clear relatively early in the HIV/AIDS pandemic and continue to this day. Not only were opportunistic infections present in a majority of HIV-infected patients who met the initial diagnostic criteria for AIDS, but several cancer types were far more prevalent as well. While there is still much to understand before HIV is fully conquered, we have already learned a great deal about the pathobiology of this virus that has helped advanced immune-oncological technologies and led to the development of increasingly effective gene therapy delivery systems.

Author | Joseph Alvarnas, MD

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