Stem Cell Transplantation in Hodgkin’s Lymphoma Past, Present and Future
Radiation critical care report to u.s. dept. of defense
1. The Untold Travesty of Nuclear
Non-Defense
I created the following slide show in 2005 at the request of Prof. Norman
Ende, M.D., who for the past ten years has tried in vain to encourage state
and federal authorities to adopt his medical blueprint for treating mass
casualties due to high dose radiation exposure.
Dr. Ende then reviewed and forwarded this slide show to Lt. Gen. P.K.
Carlton, M.D., former Air Force Surgeon General, for his presentation to the
DOD and NORAD. General Carlton called Ende’s strategy for using cord
blood as a first line of medical defense against a catastrophic nuclear
nightmare, “The only hope for those who might be saved.”
Ende’s plan reveals medical potentials that threaten a vastly lucrative
medical paradigm re the treatment of any condition requiring bone marrow
reconstitution. Hence Americans remain without a shred of medical hope
should the unthinkable occur.
J. Perry Kelly, author of “The Sibyl Reborn”
2. Radiation Injury: Critical Care
Acute radiation syndrome (ARS) is an acute
illness caused by irradiation of the whole body
(or a significant portion of it).
In general, the higher the dose the greater the
severity of early effects and the greater the
possibility of late effects.
Depending on dose, the following syndromes
can manifest:
3. 3
• Skin syndrome, characterized by loss of epidermis and
possibly dermis, called “radiation burns;” can occur with other
syndromes.
• Hematopoietic syndrome, characterized by
deficiencies of white blood count, lymphocytes and platelets,
immunodeficiency, increased infectious complications,
bleeding, anemia, and impaired wound healing; total body
exposure > 2 Gy (200 rads).
• Gastrointestinal syndrome - characterized by loss of
cells lining intestinal crypts and loss of mucosal barrier, with
alterations in intestinal motility, fluid and electrolyte loss with
vomiting and diarrhea, loss of normal intestinal bacteria,
sepsis, and damage to the intestinal microcirculation; >10 Gy
• Cerebrovascular/CNS syndrome - primarily
associated with effects on the vasculature and resultant fluid
shifts. Signs include vomiting and diarrhea within minutes of
exposure, confusion, disorientation, cerebral edema,
hypotension, and hyperpyrexia. Fatal in short time; >30 Gy
4. 4
Acute Radiation Syndrome:
Exposure Less Than 2 Gy (200 rad)
Nausea and vomiting due to radiation are seldom
experienced unless exposure is at least 0.75 Gy.
Patients without symptoms in 24 hours will most
certainly have had less than 0.75 Gy of whole-body
exposure. Hospitalization is generally unnecessary
if exposure is less than 2 Gy (200 rads).
Management of ARS (dose less than 2 Gy):
• Observation and frequent CBC with differential.
• Outpatient management may be appropriate.
• Provide instructions regarding home care.
5. 5
Acute Radiation Syndrome:
Exposure Greater than 2 Gy (200 rads)
• Prevention and treatment of infections.
• Stimulation of hematopoiesis (use of growth factors,
i.e., GCSF, GMCSF, interleukin 11).
• Stem cell transfusions: cord blood, peripheral blood,
or bone marrow. Platelet transfusions if bleeding
occurs or if platelet count too low.
• Psychological support.
• Observe carefully for erythema, hair loss, skin injury,
mucositis, parotitis, weight loss, and/or FEVER.
• Consultation with experts in radiation accident
management is encouraged.
6. 6
Hematopoietic Syndrome:
• Prodromal phase: nausea, vomiting and anorexia
within a few hours at the higher dose levels, lasts
24 to 48 hours
• Latent Phase: lasts a few days to 2-3 weeks
depending on dose. Exhibits lymphocyte
depression, and gradual decline of neutrophil and
platelet counts
• Bone Marrow Depression Phase: Infection and
hemorrhage can occur when white cell and platelet
become critically low
• Depending on exposure, Hematopoietic support
can become critical within several days to three
weeks
7. 7
Chernobyl: A Harsh Lesson
• At Chernobyl, some victims received bone
marrow that was HLA matched or partially
matched. However, donor marrows were difficult
to obtain in adequate numbers.
• After exposure to between 2 to 16 Gy, 28 of 34
service personnel died of acute bone-marrow
failure, GVHD, or gastro-intestinal infection.
• Human umbilical cord blood, now considered an
excellent source of hematopoietic stem cells, was
not used at Chernobyl.
8. 8
Bone Marrow Transplantation:
practical limitations and clinical hurdles
• Finding matched donors for numerous
casualties on short notice
• Rejection of donor marrow by residual
immune functions
• Graft Versus Host Disease (GVHD):
transplanted cells attack the host
• Increased risk of infection through
immunosuppression.
9. 9
Cord Blood for Hematopoietic
Syndrome: Benefits
• Greater genetic diversity and availability
• Reduced need for HLA-matching
• Less prone to GVHD, or host rejection
• Reduced need for immunosuppression
• Extensive clincial experience (for
hematopoietic restoration following radiation
and/or chemo for cancer)
• Easy to collect, analyze, store, and use
10. 10
Unique Points
• Cord blood’s speed of engraftment and event-free success is
directly related to the number of transplanted nucleated cells.
• Pooling unmatched units of cord blood increases densities of
nucleated blood cells, primitive (Berashis) stem cells, CD34,
CD117, and GPA cells, and increases mitotic activity
• Without raising risks of rejection, pooling unmatched cord
blood substancially reduces reactivity of CB responder cells
to fresh allogenic CB stimulator cells, likewise reducing CB
responder cell reactivity to host stimulator cells (GVHD)
• In addition to offering replacement of hematopoietic systems
destroyed by radiation, cord blood-derived hematopoietic cells
co-exist with surviving marrow cells, encouraging endogenous
hematopoietic recovery, while providing transitional support
Single units of cord blood engraft more slowly than
bone marrow from an HLA-matched bone marrow
donor, however…
11. 11
Human evidence suggestive of the previous points
“Four patients with advanced solid tumors were
treated by means of high-dose chemotherapy and
HLA-mismatched and unrelated multi-cord blood
transfusion. Of these patients, three achieved
complete remission and one achieved a partial
remission. Little or no graft vs. host disease (GVHD)
was observed. These results suggest the possibility
that HLA-mismatched and unrelated multi-cord
blood transfusion may engraft with little or no GVHD
and hasten recovery from marrow suppression.”
Shen B.-J. et.al., Blood Cells Volume 20,
Issue 2-3 , 1994, Pages 285-292
12. 12
Cord Blood –Treated Radiation Casualty
Japanese Tokaimura Facility
“Although the transplanted cord blood
cells engrafted, the patient’s bone marrow
functions eventually returned two months
later. During this period, there existed a mixed
chimerism between donor cells and recipient
cells.”
From: Radiation-Accident Preparedness: The Clinical Care of
Victims, Fourth International REAC/TS Conference on the Medical
Basis for Radiation Accident Preparedness, March 2001, Orlando FL
13. 13
Cord Blood vs. Bone Marrow
68 adult human study using single units of mismatched cord
blood compared to HLA-matched bone marrow use:
Engraftement
success:
Acute severe
GVHD:
Chronic
GVHD:
Cord Blood Bone Marrow
90% 92%
20% 35-55%
38% 55-75%
M. J. Laughlin, M.D., et.al., Hematopoietic Engraftment and Survival in Adult
Recipients of Umbilical Cord Blood from Unrelated Donors. New England
Journal of Medicine Volume 344:1815-1822 June 14, 2001 Number 24
14. 14
“In the event of large-scale exposure,
some persons are likely to be exposed to a
dose of total-body radiation (approximately 6
to 15 Gy) that would result in death from
bone marrow failure without other life-
threatening complications. The only effective
treatment for bone marrow failure caused by
lethal doses of radiation is hematopoietic-
cell transplantation.”
Continued…
In Conclusion:
15. 15
“Units of cryopreserved umbilical-cord
blood can be identified in registries and
made available for transplantation within
days. When umbilical-cord blood is used,
less stringent HLA matching is required. A
bank of approximately 200,000 units could
provide 90 percent of the population with
cord blood matched at four or five of six HLA
loci — the type of matches most commonly
used in cord-blood transplantation.”
Continued…
16. 16
“Shortening the turnaround time for
searching donor registries, providing an
umbilical-cord–blood bank of appropriate
size, and developing a consortium of
transplantation programs should be part
of the plan for national preparedness for
radiological disaster.”
Stephen J. Forman, M.D. Lawrence D. Petz, M.D.
Major Radiation Exposure, Letters; New England Journal of
Medicine, Volume 347:944-947 September 19, 2002 Number 12
17. 17
Referenced Literature:
Ricks RC, Berger ME, O’Hara FM Jr., Radiation-Accident Preparedness: The
Clinical Care of Victims, Fourth International REAC/TS Conference on the Medical
Basis for Radiation Accident Preparedness, March 2001, Orlando FL
Rubinstein, et.al., Outcomes among 562 Recipients of Placental-Blood Transplants
from unrelated donors. New England Journal of Medicine, Vol. 339, Nov. 26th,
1998, no.22 1565-77
Laughlin, et.al., Hematopoietic Engraftment and survival in adult recipients of
umbilical cord blood from unrelated donors. New England Journal of Medicine
Volume 344:1815-1822 June 14, 2001 Number 24
Ende, et.al., Potential effectiveness of stored cord blood (non-frozen) for
emergency use. The Journal of Emergency Medicine Vol 14, no.6, pp673-677 (1996)
Ende, et.al., Pooled umbilical cord blood as a possible universal donor for marrow
reconstitution and use in nuclear accidents. Life Sciences 69 (2001) 1531-1539`
Shen et.al., Unrelated, HLA-mismatched multiple human umbilical cord blood
transfusion in four cases with advanced solid tumors: Initial studies. Blood Cells
Volume 20, Issue 2-3 , 1994, Pages 285-292
18. 18
Ende et.al., The feasibility of using blood bank-stored (4°C) cord blood,
unmatched for HLA for marrow transplantation. Am J. Clin. Pathol. (1999) 111;
6: 773-781.
Gluckman, Hematopoietic Stem-Cell Transplants using umbilical-cord blood, The
New England Journal of Medicine, Vol. 344, No. 24; June 14, 2001, pg. 1860-61
Ende, et.al., Murine survival of lethal irradiation with the use of human umbilical
cord blood. Life Sci. 51:1249-1253. (1992)
Ende, N. Use of human umbilical cord blood for stem-cell transplantation (HLA-
matched, unmatched. Clinical, ethical, and legal aspects). In: Hematopoietic
Stem Cells. (1995) Edited by: D. Levitt and Mertelsmann. 333-347.
Ende et.al., The effect of human cord blood on SJL/J mice after chemoablation
and irradiation and its possible clinical significance Immunological Investigations
Volume 24, Issue 6 , November 1995, Pages 999-1012
Gluckman et.al., Clinical applications of stem cell transfusion from cord blood
and rationale for cord blood banking Bone Marrow Transplantation Volume 9,
Supplement 1 , 1992, Pages 114-117
Guidance for Radiation Accident Management: Radiation Emergency Assistance
Center/Training Site REAC/TS