Risks in Perspective |
Resources - General |
Stem Cell |
| Cardiac Toxicity |
Suppression | Myelodysplasia & AML- Leukemia
| Secondary Cancers ...
AND cardiac toxicity |
analogs AND immune suppression | Auto
SCT and secondary cancers
Effects | About Transformation
will post abstracts and resources that describe some of the more
serious risks associated with cancer therapies, primarily: secondary
cancers, myelodysplastic syndrome, and long-term immune suppression.
But we will also try to put the risks into
perspective by noting how likely they are to manifest, and in
how much time; and by
balancing the risks of treatment against the dangers of delaying or
avoiding appropriate treatments.
For example, while it's true that alkylating agents
(such as Leukeran and Cyclophosphamide) increase the risk of developing secondary cancers,
the increased risks appear to be relatively small and minimal
compared to letting the disease progress unchecked. Importantly the risks
can often take many years to emerge, often as long as 10 to 20
PubMed abstracts & Abstracts on Second Malignancies - Medscape free login req.
Alkylating agents, radiotherapy, autologous
transplants, and splenectomy increase the risk of developing MDS (Myelodysplastic Syndrome - failure of the bone marrow to produce healthy and sufficient blood cells), but the risks of developing MDS
range from small to significant ( 3 - 12%) depending on the therapy
type (Auto Transplant seems to have the highest risk), but this
approach is generally tried when the patient has aggressive and/or
Some treatments may be associated with the transformation of indolent
lymphomas to a more aggressive disease. However, be aware that associations
between specific treatment and transformation do not prove that
one caused the other, because transformation is also a part of the natural course of
It appears to be especially prudent to carefully
assess treatment-related risks when the treatment path is
unclear, as is often the case for indolent lymphomas.
Resources - General
Collecting Stem Cells following treatment
MCP Chemotherapy Regimen May Reduce Amount of Stem Cells Collected in Follicular Lymphoma
"According to results recently published in Annals of
Oncology, the chemotherapy regimen consisting of melphalan,
chlorambucil, and prednisone (MCP) appears to interfere with the
ability to collect enough stem cells for an autologous stem cell
transplant in patients with follicular non-Hodgkin’s lymphoma.
Treatment related mortality: Cytochrome
P450 2C19 loss-of-function polymorphism is associated with an
increased treatment-related mortality in patients undergoing
allogeneic transplantation. Bone Marrow Transplant. 2007
Oct;40(7):659-64. Epub 2007 Aug 6. PMID:
Comment: Probably this finding needs to be validated
(reproduced by an independent group) before being declared as
true, but it shows how normal variations in patients (a
polymorphism) can affect outcomes. In this case,
treatment-related mortality is strongly correlated with a specific
normal genetic variation
Immune suppression - Infectious Complications
Almost all treatments for lymphomas suppress or
impair immunity. The degree of immune suppression depends on many factors, including dose, dose timing, and the type of
agent. Some agents are associated with more significant immune
suppression than others. In general, younger patients are better able
to recover bone marrow function following treatment than the
"Fludarabine use in previously treated patients with CLL may be associated with infections involving T-cell dysfunction, such as listeriosis, pneumocystosis, mycobacterial infections, and opportunistic fungal and viral infections. These infections may result from T-cell depletion secondary to fludarabine use. Prophylaxis or presumptive therapy should be initiated when appropriate.
Treatment with alemtuzumab, a monoclonal antibody, affects both B cells and T cells and shows a pattern of infections similar to that of purine analogs. Varicella zoster virus, herpes simplex virus, and CMV are all common in patients with
CLL." Source: medscape.com
(free login req.)
A new model for predicting infectious complications during
fludarabine-based combination chemotherapy among patients with
indolent lymphoid malignancies. Cancer. 2004 Nov 1;101(9):2042-9. PMID:
Warning label added to Rituxan -
the label was "revised
to indicate that hepatitis B virus reactivation with fulminant
hepatitis, hepatic failure and death has been reported in some
patients with hematologic malignancies who were treated with
Rituxan since its approval." - pharmexec.com
Rituximab treatment results in impaired secondary humoral
Blood. 2002 Sep 15;100(6):2257-9. PMID:
12200395 | Related
Infectious complications associated with purine analogs (such
as fludarabine) - Related
Impact of therapy With chlorambucil, fludarabine, or
fludarabine plus chlorambucil on infections in patients with
chronic lymphocytic leukemia: Intergroup Study Cancer and Leukemia
Group B 9011.
J Clin Oncol. 2001 Aug 15;19(16):3611-21. PMID: 11504743 - PubMed
Myelodysplasia (MDS) & Leukemias
Also See Side Effects > Myelodysplastic
A "rare and potentially fatal blood disorders that occur
when the body starts incorrectly manufacturing the three types of blood cells - white, red, and platelets -
resulting in malformed, immature cells." See - Myelodysplasia
Syndromes, Basic Explanations PDF
The following "Published data suggest that the risk of
treatment-related-AML/ and treatment-related MDS following standard
chemotherapy is 1% to 1.5% per year from 2-10 years after initiation
Leukemogenic therapies are agents that
increase the risk of developing leukemias. - "The risk of
leukemia was greatest four or five years after chemotherapy began,
and the risk was elevated for at least eight years after the
cessation of chemotherapy. The drugs cyclophosphamide, chlorambucil,
melphalan, thiotepa, and treosulfan were independently associated
with significantly increased risks of leukemia, as was the
combination of doxorubicin hydrochloride and cisplatin. Chlorambucil
and melphalan were the most leukemogenic drugs, followed by thiotepa;
cyclophosphamide and treosulfan were the weakest leukemogens, and
the effect per gram was substantially lower at high doses than at
lower doses. The extent to which the relative risks of leukemia are
offset by differences in chemotherapeutic effectiveness is not
NEW Secondary malignancies after therapy of indolent
Haematologica 2008 93: 336-338., Jonathan W. Friedberg - full text
Second malignancies have clearly evolved to be
important causes of morbidity and mortality in patients
with indolent lymphomas. As survival times increase,
and the cohort of patients treated with modalities such
as purine analogs, aggressive autologous transplantation
and novel radioimmunotherapy grows, it can be expected
that the incidence of second cancers will increase significantly.
Perhaps most concerning is the lack of an apparent plateau
in the incidence curve, even 20–30 years after diagnosis
of lymphoma. For this reason, it is critical that patients
in prolonged remission remain under care of medical and
radiation oncologists attuned to these risks, and undergo at
least annual evaluation (history and physical examinations), with
appropriate screening tests for second cancers. In the future,
emphasis must continue to be given to minimizing toxic therapy
to prevent this devastating cost of cure.26
Finally, it is important to realize that the risk of
MDS/AML associated with radioimmunotherapy may not be
substantially different from the risk in patients
treated with standard chemotherapy, including both
alkylating agents and purine analogs.
RIT and risk of MDS:
Treatment-related myelodysplastic syndrome (MDS) and AML in
patients treated with Zevalin radioimmunotherapy. J Clin Oncol.
2007 Sep 20;25(27):4285-92. Epub 2007 Aug 20.
Analysis of data from patients ... (746 patients) ...
incidences of t-MDS and t-AML (0.7% per year after treatment) are
consistent with that expected in patients with NHL who have had
extensive previous chemotherapy treatment and do not appear to be
increased after treatment with the ibritumomab tiuxetan regimen.
Myelodysplasia and acute myeloid leukemia following therapy
for indolent lymphoma with fludarabine, mitoxantrone, and
dexamethasone (FND) plus rituximab and interferon alpha - bloodjournal.org
Specific Regimen [FND] Influences Risk of Myelodysplasia After
Lymphoma Treatment - Medscape
(free login req.) or ASCO
Armitage JO, Carbone PP, Connors JM, et al.
Treatment-related myelodysplasia and
acute leukemia in non-Hodgkin's lymphoma patients. J Clin Oncol.
Secondary myelodysplasia following purine analog therapy - Abstract
Therapy-related myeloid leukemias are observed in patients
with chronic lymphocytic leukemia after treatment with fludarabine
and chlorambucil: results of an intergroup study, cancer and
leukemia group B 9011. J Clin Oncol. 2002 Sep 15;20(18):3878-84.
PMID: 12228208 - PubMed
Treatment-Related Myelodysplasia and Acute Leukemia in
Non-Hodgkin's Lymphoma Patients. J Clin Oncol. 2003 Mar
1;21(5):897-906. PMID: 12610191 - PubMed |
Secondary Cancers in Lymphoma Survivors
* JCO, 2010:
Second Malignant Neoplasms in Survivors of Pediatric Hodgkin's
Lymphoma Treated With Low-Dose Radiation and Chemotherapy
Cumulative incidence of first
second malignant neoplasms (SMN) was 17% (95% CI, 10.5 to 26.7)
at 20 years after HL diagnosis. The standard incidence ratio (SIR*)
for any second malignancy was 22.9 (95% CI, 14.2 to 35) with an
absolute excess risk of 93.7 cases per 10,000 person-years.
Standard Incidence ratio (SIR):
"The expected number is calculated by multiplying each
age-specific cancer incidence rate of the reference population
by each age-specific population of the community in question and
then adding up the results. If the observed number of cancer
cases equals the expected number, the SIR is 1. If more cases
are observed than expected, the SIR is greater than 1. If fewer
cases are observed than expected, the SIR is less than 1.
malignancies after therapy of indolent non-Hodgkin’s lymphoma
Jonathan W. Friedberg
The true incidence of MDS/AML and
other secondary malignancies after treatment for indolent
lymphoma, outside of the setting of autologous transplantation,
is largely unknown. Historical series have suggested that the
incidence of secondary malignancies is almost double the
expected incidence over a 10-year follow-up period and patients
treated with total body irradiation have an even higher
Secondary Malignancies: What, When, Why, in Whom? -
Bhatia, MD, MPH
NCCN Clinical Practice Oncology Forum. 2008; ©2008 NCCN Clinical Practice Oncology Forum
The growing population of cancer survivors carries a
significant burden of morbidity, necessitating comprehensive
long-term follow-up, which should ideally begin at the completion
of active therapy.
Documentation of therapeutic exposures will form the basis for use
of recommendations within the long-term follow-up guidelines, thus
ensuring standardization of care received by the survivors.
However, many barriers prevent effective follow-up, the most
fundamental of which are the lack of understanding by long-term
survivors about their risk, as well as by the primary care
physicians caring for them.
Shortcomings of the healthcare system are also potential barriers
to long-term follow-up, and include infrastructure issues, such as
a lack of capacity within centers, training and educational
deficiencies, and inadequate/ineffective communication between
oncologists and primary care physicians who subsequently provide
the large bulk of follow-up care.
Risk factors for development of a second lymphoid malignancy in patients with
Br J Haematol. 2007 Nov;139(3):398-404. PMID: 17910629
The risk of secondary malignancies over 30 years
after the treatment of non-Hodgkin lymphoma.
Cancer. 2006 May 17; PMID:
16708354 | Related
Cancer risk higher in lymphoma survivors -
"Survivors had an 8.8-fold increased risk of leukemia and a
1.6-fold risk of lung cancer, according to the report in the
Journal of Clinical Oncology"
Risk of Second Malignancy After Non-Hodgkin's Lymphoma: A
British Cohort Study.
J Clin Oncol. 2006 Mar 6; [Epub ahead of print] PMID:
16520465 | Related
Researchers Learn More About Secondary Cancers After Non-Hodgkin's Lymphoma
Second cancers among long-term survivors of non-Hodgkin's
J Natl Cancer Inst. 1993 Dec 1;85(23):1932-7. PMID:
Risk of leukemia following treatment for non-Hodgkin's
lymphoma - jncicancerspectrum.oxfordjournals.org/
"Our results suggest that prednimustine may be
a human carcinogen, with a positive dose-response gradient evident
for ANLL risk. The low, nonsignificant risk of leukemia
associated with cyclophosphamide was reassuring because
this drug is commonly used today. Despite the excesses
of ANLL associated with specific therapies, secondary leukemia
remains a rare occurrence following NHL. Of 10,000 NHL patients
treated for 6 months with selected regimens including low
cumulative doses of cyclophosphamide and followed for
10 years, an excess of four leukemias might be
AAOS: Increased Rate of Secondary Cancers Seen in Long-Term
Osteosarcoma Survivors - pslgroup.com
MEDLINE Abstracts: Second Malignancies from Medscape Hematology-Oncology
What's new about therapy-related malignancies in cancer patients? -
Medscape free login req.
New malignancies after blood or marrow stem-cell
transplantation in children and adults: incidence and risk
factors. J Clin Oncol. 2003 Apr 1;21(7):1352-8. Erratum in: J Clin
Oncol. 2003 Aug 15;21(16):3181.
12663726 | Abstracts
Researchers Learn More About Secondary Cancers After Non-Hodgkin’s Lymphoma
" Researchers concluded that secondary cancers after NHL are
often treatment-related, but other sources, such as immune
suppression and environmental exposures, may also play a role in
the development of secondary cancers and malignancies."
Second cancers and late toxicities after treatment of
aggressive non-Hodgkin lymphoma - bloodjournal.org
It is prudent to check for
melanoma often if you have lymphoma.
Visible Warning Signs (ABCDE's):
If you have any of the above features - or anything else out
of the ordinary - show your doctor as soon as possible.
Source: RITE AID pharmacy
See About transformation
Large-cell transformation of chronic lymphocytic leukemia and
follicular lymphoma during or soon after treatment with
fludarabine-rituximab-containing regimens: natural history- or
therapy-related complication? Eur J Haematol. 2002 Feb;68(2):80-3.
PMID: 12038452 - PubMed